U.S. patent application number 10/509732 was filed with the patent office on 2005-06-30 for carbamic acid compounds comprising a piperazine linkage as hdac inhibitors.
Invention is credited to Dikovska, Klar, Finn, Paul W., Gailite, Vija, Kalvinsh, Ivars, Lolya, Daina, Loza, Einars, Ritchie, James, Romero-Martin, Maria-Rosario, Starchenkov, Igor, Watkins, Clare J..
Application Number | 20050143385 10/509732 |
Document ID | / |
Family ID | 28675576 |
Filed Date | 2005-06-30 |
United States Patent
Application |
20050143385 |
Kind Code |
A1 |
Watkins, Clare J. ; et
al. |
June 30, 2005 |
Carbamic acid compounds comprising a piperazine linkage as hdac
inhibitors
Abstract
This invention pertains to certain carbamic acid compounds which
inhibit HDAC (histone deacetylase) activity of the following
formula: 1 wherein: Cy is independently a cyclyl group; Q.sup.1 is
independently a covalent bond or cyclyl leader group; the
piperazin-1,4-diyl group is optionally substituted; J.sup.1 is
independently a covalent bond or --C(.dbd.;O)--; J.sup.2 is
independently --C(.dbd.O)-- or --S(.dbd.O).sub.2--; Q.sub.2 is
independently an acid leader group; wherein: Cy is independently:
C.sub.3-20carbocyclyl, C.sub.3-20heterocyclyl, or C.sub.5-20aryl;
and is optionally substituted; Q.sup.1 is independently: a covalent
bond; C.sub.1-7alkylene; or C.sub.1-7alkylene-X--C.sub.1-7alkylene,
--X--C.sup.1-7alkylene, or C.sub.1-7alkylene-X--, wherein X is
--O-- or --S--; and is optionally substituted; Q.sup.2 is
independently: C.sub.4-8alkylene; and is optionally substituted;
and has a backbone length of at least 4 atoms; or: Q.sup.2 is
independently: C.sub.5-20arylene; C.sub.5-20arylene-C.sub.-
1-7alkylene; C.sub.1-7alkylene-C.sub.5-20arylene; or,
C.sub.1-7alkylene-C.sub.5-20arylene-C.sub.1-7alkylene; and is
optionally substituted; and has a backbone length of at least 4
atoms; or a pharmaceutically acceptable salt, solvate, amide,
ester, ether, chemically protected form, or prodrug thereof. The
present invention also pertains to pharmaceutical compositions
comprising such compounds, and the use of such compounds and
compositions, both in vitro and in vivo, to inhibit HDAC, and in
the treatment of conditions mediated by HDAC, cancer, proliferative
conditions, psoriasis, etc.
Inventors: |
Watkins, Clare J.;
(Abingdon, GB) ; Romero-Martin, Maria-Rosario;
(Didcot, GB) ; Ritchie, James; (Abingdon, GB)
; Finn, Paul W.; (Abingdon, GB) ; Kalvinsh,
Ivars; (Riga, LV) ; Loza, Einars; (Riga,
LV) ; Dikovska, Klar; (Riga, LV) ;
Starchenkov, Igor; (Riga, LV) ; Lolya, Daina;
(Riga, LV) ; Gailite, Vija; (Riga, LV) |
Correspondence
Address: |
NIXON & VANDERHYE, PC
1100 N GLEBE ROAD
8TH FLOOR
ARLINGTON
VA
22201-4714
US
|
Family ID: |
28675576 |
Appl. No.: |
10/509732 |
Filed: |
September 30, 2004 |
PCT Filed: |
April 3, 2003 |
PCT NO: |
PCT/GB03/01463 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60369337 |
Apr 3, 2002 |
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|
Current U.S.
Class: |
514/252.12 ;
514/252.13; 544/359; 544/399 |
Current CPC
Class: |
A61P 35/00 20180101;
C07D 239/42 20130101; A61P 25/28 20180101; A61P 43/00 20180101;
C07D 295/192 20130101; A61P 25/16 20180101; C07D 213/74 20130101;
C07D 317/58 20130101; C07D 333/60 20130101; C07D 295/26 20130101;
C07D 295/185 20130101; A61P 17/06 20180101 |
Class at
Publication: |
514/252.12 ;
514/252.13; 544/359; 544/399 |
International
Class: |
A61K 031/496; A61K
031/495; C07D 043/02 |
Claims
1. A compound of the formula: 183wherein: Cy is independently a
cyclyl group; Q.sup.1 is independently a covalent bond or cyclyl
leader group; the piperazin-1,4-diyl group is optionally
substituted; J.sup.1 is independently a covalent bond or
--C(.dbd.O)--; J.sup.2 is independently --C(.dbd.O)-- or
--S(.dbd.O)2--; Q.sup.2 is independently an acid leader group;
wherein: Cy is independently: C.sub.3-20carbocyclyl,
C.sub.3-20heterocyclyl, or C.sub.5-20aryl; and is optionally
substituted; Q.sup.1 is independently: a covalent bond;
C.sub.1-7alkylene; or C.sub.1-7alkylene-X--C.sub.1-7alkylene,
--X--C.sub.1-7alkylene, or C.sub.1-7alkylene-X--, wherein X is
--O-- or --S--; and is optionally substituted; Q.sup.2 is
independently: C.sub.4-8alkylene; and is optionally substituted;
and has a backbone length of at least 4 atoms; or: Q.sup.2 is
independently: C.sub.5-20arylene; C.sub.5-20arylene-C.sub.-
1-7alkylene; C.sub.1-7alkylene-C.sub.5-20arylene; or,
C.sub.1-7alkylene-C.sub.5-20arylene-C.sub.1-7alkylene; and is
optionally substituted; and has a backbone length of at least 4
atoms; or a pharmaceutical acceptable salt, solvate, amide, ester,
ether, chemically protected form, or prodrug thereof.
2-79. (canceled)
80. A compound of the formula: 184wherein: Cy is independently a
cyclyl group; Q.sup.1 is independently a covalent bond or cyclyl
leader group; the piperazin-1,4-diyl group is optionally
substituted; J.sup.1 is independently a covalent bond or
--C(.dbd.O)--; J.sup.2 is independently --C(.dbd.O)-- or
--S(.dbd.O).sub.2--; Q.sup.2 is independently an acid leader group;
wherein: Cy is independently: C.sub.3-20carbocyclyl,
C.sub.3-20heterocyclyl, or C.sub.5-20aryl; and is optionally
substituted; Q.sup.1 is independently: a covalent bond;
C.sub.1-7alkylene; or C.sub.1-7alkylene-X--C.sub.1-7alkylene,
--X--C.sub.1-7alkylene, or C.sub.1-7alkylene-X--, wherein X is
--O-- or --S--; and is optionally substituted; Q.sup.2 is
independently: C.sub.4-8alkylene; and is optionally substituted;
and has a backbone length of at least 4 atoms; or: Q.sup.2 is
independently: C.sub.5-20arylene; C.sub.5-20arylene-C.sub.-
1-7alkylene; C.sub.1-7alkylene-C.sub.5-20arylene; or,
C.sub.1-7alkylene-C.sub.5-20arylene-C.sub.1-7alkylene; and is
optionally substituted; and has a backbone length of at least 4
atoms; or a pharmaceutically acceptable salt, solvate, amide,
ester, ether, chemically protected form, or prodrug thereof.
81. A compound according to claim 80, wherein the
piperazin-1,4-diyl group is unsubstituted or substituted at one or
more the 2-, 3-, 5-, and 6-positions with C.sub.1-4alkyl.
82. A compound according to claim 80, wherein: J.sup.1 is a
covalent bond; and J.sup.2 is --C(.dbd.O)--.
83. A compound according to claim 80, wherein: J.sup.1 is
--C(.dbd.O)--; and J.sup.2 is --C(.dbd.O)--.
84. A compound according to claim 80, wherein: J.sup.1 is a
covalent bond; and J.sup.2 is --S(.dbd.O).sub.2--.
85. A compound according to claim 80, wherein Q.sup.1 is
independently: a covalent bond; or a cyclyl leader group; and is
optionally substituted.
86. A compound according to claim 80, wherein Q.sup.1 is
independently a cyclyl leader group, and is optionally
substituted.
87. A compound according to claim 80, wherein Q.sup.1 is
independently C.sub.1-7alkylene, and is optionally substituted.
88. A compound according to claim 80, wherein: Q.sup.1 is
independently C.sub.1-7alkylene, and is optionally substituted;
J.sup.1 is independently a covalent bond; J.sup.2 is independently
--C(.dbd.O)--.
89. A compound according to claim 80, wherein: Q.sup.1 is
independently C.sub.1-7alkylene, and is optionally substituted;
J.sup.1 is independently --C(.dbd.O)--; J.sup.2 is independently
--C(.dbd.O)--.
90. A compound according to claim 80, wherein: Q.sup.1 is
independently C.sub.1-7alkylene, and is optionally substituted;
J.sup.1 is independently a covalent bond; J.sup.2 is independently
--S(.dbd.O).sub.2--.
91. A compound according to claim 80, wherein: Q.sup.1 is
independently C.sub.1-7alkylene, and is optionally substituted;
J.sup.1 is independently --C(.dbd.O)--; J.sup.2 is independently
--S(.dbd.O).sub.2--.
92. A compound according to claim 80, wherein Q.sup.1 is
independently C.sub.1-3alkylene, and is optionally substituted.
93. A compound according to claim 80, wherein Q.sup.1 is
independently: C.sub.1-7alkylene-X--C.sub.1-7alkylene,
--X--C.sub.1-7alkylene, or C.sub.1-7alkylene-X--; wherein X is
--O-- or --S--; and is optionally substituted.
94. A compound according to claim 80, wherein Q.sup.1 is
independently: C.sub.1-3alkylene-X--C.sub.1-3alkylene,
--X--C.sub.1-3alkylene, or C.sub.1-3alkylene-X--; wherein X is
--O-- or --S--; and is optionally substituted.
95. A compound according to claim 80, wherein substituents on
Q.sup.1, if present, are independently: halo, hydroxy, ether,
C.sub.5-20aryl, acyl, amino, amido, acylamido, or oxo.
96. A compound according to claim 80, wherein substituents on
Q.sup.1, if present, are independently: --F, --Cl, --Br, --I, --OH,
--OMe, --OEt, --OPr, -Ph, --NH.sub.2, --CONH.sub.2, or .dbd.O.
97. A compound according to claim 80, wherein Q.sup.1, if other
than a covalent bond, is unsubstituted.
98. A compound according to claim 80, wherein Q.sup.1 is
independently a covalent bond.
99. A compound according to claim 80, wherein: Q.sup.1 is
independently a covalent bond; J.sup.1 is independently a covalent
bond; J.sup.2 is independently --C(.dbd.O)--.
100. A compound according to claim 80, wherein: Q.sup.1 is
independently a covalent bond; J.sup.1 is independently
--C(.dbd.O)--; J.sup.2 is independently --C(.dbd.O)--.
101. A compound according to claim 80, wherein: Q.sup.1 is
independently a covalent bond; J.sup.1 is independently a covalent
bond; J.sup.2 is independently --S(.dbd.O).sub.2--.
102. A compound according to claim 80, wherein: Q.sup.1 is
independently a covalent bond; J.sup.1 is independently
--C(.dbd.O)--; J.sup.2 is independently --S(.dbd.O).sub.2--.
103. A compound according to claim 80, wherein Q.sup.2 is
independently: C.sub.4-8alkylene; and is optionally substituted;
and has a backbone length of at least 4 atoms.
104. A compound according to claim 80, wherein Q.sup.2 is
independently a saturated aliphatic C.sub.4-8alkylene group.
105. A compound according to claim 88, wherein Q.sup.2 is
independently a saturated aliphatic C.sub.4-8alkylene group.
106. A compound according to claim 89, wherein Q.sup.2 is
independently a saturated aliphatic C.sub.4-8alkylene group.
107. A compound according to claim 90, wherein Q.sup.2 is
independently a saturated aliphatic C.sub.4-8alkylene group.
108. A compound according to claim 91, wherein Q.sup.2 is
independently a saturated aliphatic C.sub.4-8alkylene group.
109. A compound according to claim 99, wherein Q.sup.2 is
independently a saturated aliphatic C.sub.4-8alkylene group.
110. A compound according to claim 100, wherein Q.sup.2 is
independently a saturated aliphatic C.sub.4-8alkylene group.
111. A compound according to claim 101, wherein Q.sup.2 is
independently a saturated aliphatic C.sub.4-8alkylene group.
112. A compound according to claim 102, wherein Q.sup.2 is
independently a saturated aliphatic C.sub.4-8alkylene group.
113. A compound according to claim 80, wherein Q.sup.2 is
independently a saturated linear C.sub.4-8alkylene group.
114. A compound according to claim 80, wherein Q.sup.2 is
independently selected from: --(CH.sub.2).sub.5--;
--(CH.sub.2).sub.6--; --(CH.sub.2).sub.7--; --(CH.sub.2).sub.8--;
--CH(CH.sub.3)CH.sub.2CH.sub.- 2CH.sub.2CH.sub.2--;
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.3)--;
--CH.sub.2CH.sub.2CH.sub.2CH.dbd.CH--; and,
--CH.sub.2CH.sub.2CH.sub.2CH.- sub.2CH.dbd.CH--.
115. A compound according to claim 80, wherein Q.sup.2 is
independently selected from: --(CH.sub.2).sub.5--,
--(CH.sub.2).sub.6--, --(CH.sub.2).sub.7--, and
--(CH.sub.2).sub.8--.
116. A compound according to claim 80, wherein Q.sup.2, is
independently: C.sub.5-20arylene;
C.sub.5-20arylene-C.sub.1-7alkylene;
C.sub.1-7alkylene-C.sub.5-20arylene;
C.sub.1-7alkylene-C.sub.5-20arylene-- C.sub.1-7alkylene; or, and is
optionally substituted; and has a backbone length of at least 4
atoms.
117. A compound according to claim 80, wherein Q.sup.2, is
independently: C.sub.5-20arylene; and is optionally substituted;
and has a backbone length of at least 4 atoms.
118. A compound according to claim 80, wherein Q.sup.2, is
independently: C.sub.5-20arylene-C.sub.1-7alkylene;
C.sub.1-7alkylene-C.sub.5-20arylene;
C.sub.1-7alkylene-C.sub.5-20arylene-C.sub.1-7alkylene; or, and is
optionally substituted; and has a backbone length of at least 4
atoms.
119. A compound according to claim 80, wherein Q.sup.2, is
independently: C.sub.5-6arylene-C.sub.1-7alkylene;
C.sub.1-7alkylene-C.sub.5-6arylene; or,
C.sub.1-7alkylene-C.sub.5-6arylene-C.sub.1-7alkylene; and is
optionally substituted; and has a backbone length of at least 4
atoms.
120. A compound according to claim 80, wherein Q.sup.2, is
independently: phenylene-C.sub.1-7alkylene;
C.sub.1-7alkylene-phenylene; or,
C.sub.1-7alkylene-phenylene-C.sub.1-7alkylene; and is optionally
substituted; and has a backbone length of at least 4 atoms.
121. A compound according to claim 80, wherein Q.sup.2, is
independently: methylene-phenylene; ethylene-phenylene;
phenylene-methylene; phenylene-ethylene; phenylene-ethenylene;
methylene-phenylene-methylene; methylene-phenylene-ethylene;
methylene-phenylene-ethenylene; ethylene-phenylene-methylene;
ethylene-phenylene-ethylene; ethylene-phenylene-ethenylene; and is
optionally substituted; and has a backbone length of at least 4
atoms.
122. A compound according to claim 88, wherein Q.sup.2, is
independently: methylene-phenylene; ethylene-phenylene;
phenylene-methylene; phenylene-ethylene; phenylene-ethenylene;
methylene-phenylene-methylene; methylene-phenylene-ethylene;
methylene-phenylene-ethenylene; ethylene-phenylene-methylene;
ethylene-phenylene-ethylene; ethylene-phenylene-ethenylene; and is
optionally substituted; and has a backbone length of at least 4
atoms.
123. A compound according to claim 89, wherein Q.sup.2, is
independently: methylene-phenylene; ethylene-phenylene;
phenylene-methylene; phenylene-ethylene; phenylene-ethenylene;
methylene-phenylene-methylene; methylene-phenylene-ethylene;
methylene-phenylene-ethenylene; ethylene-phenylene-methylene;
ethylene-phenylene-ethylene; ethylene-phenylene-ethenylene; and is
optionally substituted; and has a backbone length of at least 4
atoms.
124. A compound according to claim 90, wherein Q.sup.2, is
independently: methylene-phenylene; ethylene-phenylene;
phenylene-methylene; phenylene-ethylene; phenylene-ethenylene;
methylene-phenylene-methylene; methylene-phenylene-ethylene;
methylene-phenylene-ethenylene; ethylene-phenylene-methylene;
ethylene-phenylene-ethylene; ethylene-phenylene-ethenylene; and is
optionally substituted; and has a backbone length of at least 4
atoms.
125. A compound according to claim 91, wherein Q.sup.2, is
independently: methylene-phenylene; ethylene-phenylene;
phenylene-methylene; phenylene-ethylene; phenylene-ethenylene;
methylene-phenylene-methylene; methylene-phenylene-ethylene;
methylene-phenylene-ethenylene; ethylene-phenylene-methylene;
ethylene-phenylene-ethylene; ethylene-phenylene-ethenylene; and is
optionally substituted; and has a backbone length of at least 4
atoms.
126. A compound according to claim 99, wherein Q.sup.2, is
independently: methylene-phenylene; ethylene-phenylene;
phenylene-methylene; phenylene-ethylene; phenylene-ethenylene;
methylene-phenylene-methylene; methylene-phenylene-ethylene;
methylene-phenylene-ethenylene; ethylene-phenylene-methylene;
ethylene-phenylene-ethylene; ethylene-phenylene-ethenylene; and is
optionally substituted; and has a backbone length of at least 4
atoms.
127. A compound according to claim 100, wherein Q.sup.2, is
independently: methylene-phenylene; ethylene-phenylene;
phenylene-methylene; phenylene-ethylene; phenylene-ethenylene;
methylene-phenylene-methylene; methylene-phenylene-ethylene;
methylene-phenylene-ethenylene; ethylene-phenylene-methylene;
ethylene-phenylene-ethylene; ethylene-phenylene-ethenylene; and is
optionally substituted; and has a backbone length of at least 4
atoms.
128. A compound according to claim 101, wherein Q.sup.2, is
independently: methylene-phenylene; ethylene-phenylene;
phenylene-methylene; phenylene-ethylene; phenylene-ethenylene;
methylene-phenylene-methylene; methylene-phenylene-ethylene;
methylene-phenylene-ethenylene; ethylene-phenylene-methylene;
ethylene-phenylene-ethylene; ethylene-phenylene-ethenylene; and is
optionally substituted; and has a backbone length of at least 4
atoms.
129. A compound according to claim 102, wherein Q.sup.2, is
independently: methylene-phenylene; ethylene-phenylene;
phenylene-methylene; phenylene-ethylene; phenylene-ethenylene;
methylene-phenylene-methylene; methylene-phenylene-ethylene;
methylene-phenylene-ethenylene; ethylene-phenylene-methylene;
ethylene-phenylene-ethylene; ethylene-phenylene-ethenylene; and is
optionally substituted; and has a backbone length of at least 4
atoms.
130. A compound according to claim 120, wherein the phenylene
linkage is meta or para.
131. A compound according to claim 120, wherein the phenylene
linkage is meta.
132. A compound according to claim 120, wherein the phenylene
linkage is para.
133. A compound according to claim 80, wherein Q.sup.2, is
independently: 185
134. A compound according to claim 80, wherein Q.sup.2, is
independently: 186
135. A compound according to claim 80, wherein Q.sup.2 is
substituted.
136. A compound according to claim 80, wherein substituents on
Q.sup.2, if present, are independently: (1) ester; (2) amido; (3)
acyl; (4) halo; (5) hydroxy; (6) ether; (7) substituted or
unsubstituted C.sub.1-7alkyl (8) substituted or unsubstituted
C.sub.5-20aryl; (9) sulfonyl; (10) sulfonamido; (11) amino; (12)
morpholino; (13) nitro; and (14) cyano.
137. A compound according to claim 80, wherein substituents on
Q.sup.2, if present, are independently: (1) --C(.dbd.O)OMe,
--C(.dbd.O)OEt, --C(.dbd.O)O(Pr), --C(.dbd.O)O(iPr),
--C(.dbd.O)O(nBu), --C(.dbd.O)O(sBu), --C(.dbd.O)O(iBu),
--C(.dbd.O)O(tBu), --C(.dbd.O)O(nPe);
--C(.dbd.O)OCH.sub.2CH.sub.2OH, --C(.dbd.O)OCH.sub.2CH.sub.2OMe,
--C(.dbd.O)OCH.sub.2CH.sub.2OEt; (2) --(C.dbd.O)NH.sub.2,
--(C.dbd.O)NMe.sub.2, --(C.dbd.O)NEt.sub.2,
--(C.dbd.O)N(iPr).sub.2, --(C.dbd.O)N(CH.sub.2CH.sub.2OH).sub.2;
(3) --(C.dbd.O)Me, --(C.dbd.O)Et, --(C.dbd.O)-cHex, --(C.dbd.O)Ph;
(4) --F, --Cl, --Br, --I; (5) --OH; (6) --OMe, --OEt, --O(iPr),
--O(tBu), --OPh; --OCF.sub.3, --OCH.sub.2CF.sub.3;
--OCH.sub.2CH.sub.2OH, --OCH.sub.2CH.sub.2OMe,
--OCH.sub.2CH.sub.2OEt; --OCH.sub.2CH.sub.2NH.sub- .2,
--OCH.sub.2CH.sub.2NMe.sub.2, --OCH.sub.2CH.sub.2N(iPr).sub.2;
--OPh, --OPh-Me, --OPh-OH, --OPh-OMe, O-Ph-F, --OPh-Cl, --OPh-Br,
--OPh-1; (7)-Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, -nPe;
--CF.sub.3, --CH.sub.2CF.sub.3; --CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2OMe, --CH.sub.2CH.sub.2OEt;
--CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2NMe.sub.2,
--CH.sub.2CH.sub.2N(iPr).sub.2; --CH.sub.2-Ph; (8)-Ph, -Ph-Me,
-Ph-OH, -Ph-OMe, -Ph-F, -Ph-Cl, -Ph-Br, -Ph-I; (9) --SO.sub.2Me,
--SO.sub.2Et, --SO.sub.2Ph; (10) --SO.sub.2NH.sub.2,
--SO.sub.2NMe.sub.2, --SO.sub.2NEt.sub.2; (11) --NMe.sub.2,
--NEt.sub.2; (12) morpholino; (13) --NO.sub.2; and (14) --CN.
138. A compound according to claim 80, wherein Q.sup.2 is
unsubstituted.
139. A compound according to claim 80, wherein Q.sup.2 has a
backbone of at least 5 atoms.
140. A compound according to claim 80, wherein Q.sup.2 has a
backbone of at least 6 atoms.
141. A compound according to claim 80, wherein Cy is independently
C.sub.3-20carbocyclyl; and is optionally substituted.
142. A compound according to claim 80, wherein Cy is independently
C.sub.3-20carbocyclyl derived from one of the following:
cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene,
cyclohexene, norbornane, adamantane, cyclopentanone, and
cyclohexanone; and is optionally substituted.
142. A compound according to claim 80, wherein Cy is independently
C.sub.3-20heterocyclyl; and is optionally substituted.
144. A compound according to claim 80, wherein Cy is independently
C.sub.3-20heterocyclyl derived from one of the following:
piperidine, azepine, tetrahydropyran, morpholine, azetidine,
piperazine, imidazoline, piperazinedione, and oxazolinone; and is
optionally substituted.
145. A compound according to claim 80, wherein Cy is independently
C.sub.5-20aryl; and is optionally substituted.
146. A compound according to claim 80, wherein Cy is independently
C.sub.5-20carboaryl or C.sub.5-20heteroaryl; and is optionally
substituted.
147. A compound according to claim 105, wherein Cy is independently
C.sub.5-20carboaryl or C.sub.5-20heteroaryl; and is optionally
substituted.
148. A compound according to claim 106, wherein Cy is independently
C.sub.5-20carboaryl or C.sub.5-20heteroaryl; and is optionally
substituted.
149. A compound according to claim 107, wherein Cy is independently
C.sub.5-20carboaryl or C.sub.5-20heteroaryl; and is optionally
substituted.
150. A compound according to claim 108, wherein Cy is independently
C.sub.5-20carboaryl or C.sub.5-20heteroaryl; and is optionally
substituted.
151. A compound according to claim 109, wherein Cy is independently
C.sub.5-20carboaryl or C.sub.5-20heteroaryl; and is optionally
substituted.
152. A compound according to claim 110, wherein Cy is independently
C.sub.5-20carboaryl or C.sub.5-20heteroaryl; and is optionally
substituted.
153. A compound according to claim 111, wherein Cy is independently
C.sub.5-20carboaryl or C.sub.5-20heteroaryl; and is optionally
substituted.
154. A compound according to claim 112, wherein Cy is independently
C.sub.5-20carboaryl or C.sub.5-20heteroaryl; and is optionally
substituted.
155. A compound according to claim 122, wherein Cy is independently
C.sub.5-20carboaryl or C.sub.5-20heteroaryl; and is optionally
substituted.
156. A compound according to claim 123, wherein Cy is independently
C.sub.5-20carboaryl or C.sub.5-20heteroaryl; and is optionally
substituted.
157. A compound according to claim 124, wherein Cy is independently
C.sub.5-20carboaryl or C.sub.5-20heteroaryl; and is optionally
substituted.
158. A compound according to claim 125, wherein Cy is independently
C.sub.5-20carboaryl or C.sub.5-20heteroaryl; and is optionally
substituted.
159. A compound according to claim 126, wherein Cy is independently
C.sub.5-20carboaryl or C.sub.5-20heteroaryl; and is optionally
substituted.
160. A compound according to claim 127, wherein Cy is independently
C.sub.5-20carboaryl or C.sub.5-20heteroaryl; and is optionally
substituted.
161. A compound according to claim 128, wherein Cy is independently
C.sub.5-20carboaryl or C.sub.5-20heteroaryl; and is optionally
substituted.
162. A compound according to claim 129, wherein Cy is independently
C.sub.5-20carboaryl or C.sub.5-20heteroaryl; and is optionally
substituted.
163. A compound according to claim 80, wherein Cy is independently
C.sub.5-20aryl derived from one of the following: benzene,
pyridine, furan, indole, pyrrole, imidazole, pyrimidine, pyrazine,
pyridizine, naphthalene, quinoline, indole, benzimidazole,
benzothiofuran, fluorene, acridine, and carbazole; and is
optionally substituted.
164. A compound according to claim 80, wherein Cy is independently
an optionally substituted phenyl group.
165. A compound according to claim 80, wherein Cy is optionally
substituted with one or more substituents selected from: (1) ester;
(2) amido; (3) acyl; (4) halo; (5) hydroxy; (6) ether; (7)
substituted or unsubstituted C.sub.1-7alkyl; (8) substituted or
unsubstituted C.sub.5-20aryl; (9) sulfonyl; (10) sulfonamido; (11)
amino; (12) morpholino; (13) nitro; and (14) cyano.
166. A compound according to claim 80, wherein Cy is optionally
substituted with one or more substituents selected from: (1)
--C(.dbd.O)OMe, --C(.dbd.O)OEt, --C(.dbd.O)O(Pr),
--C(.dbd.O)O(iPr), --C(.dbd.O)O(nBu), --C(.dbd.O)O(sBu),
--C(.dbd.O)O(iBu), --C(.dbd.O)O(tBu), --C(.dbd.O)O(nPe);
--C(.dbd.O)OCH.sub.2CH.sub.2OH, --C(.dbd.O)OCH.sub.2CH.sub.2OMe,
--C(.dbd.O)OCH.sub.2CH.sub.2OEt; (2) --(C.dbd.O)NH.sub.2,
--(C.dbd.O)NMe.sub.2, --(C.dbd.O)NEt.sub.2,
--(C.dbd.O)N(iPr).sub.2, --(C.dbd.O)N(CH.sub.2CH.sub.2OH).sub.2;
(3) --(C.dbd.O)Me, --(C.dbd.O)Et, --(C.dbd.O)-cHex, --(C.dbd.O)Ph;
(4) --F, --Cl, --Br, --I; (5) --OH; (6) --OMe, --OEt, --O(iPr),
--O(tBu), --OPh; --OCF.sub.3, --OCH.sub.2CF.sub.3;
--OCH.sub.2CH.sub.2OH, --OCH.sub.2CH.sub.2OMe,
--OCH.sub.2CH.sub.2OEt; --OCH.sub.2CH.sub.2NH.sub- .2,
--OCH.sub.2CH.sub.2NMe.sub.2, --OCH.sub.2CH.sub.2N(iPr).sub.2;
--OPh, --OPh-Me, --OPh-OH, --OPh-OMe, O-Ph-F, --OPh-CI, --OPh-Br,
--OPh-I; (7)-Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, -nPe;
--CF.sub.3, --CH.sub.2CF.sub.3; --CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2OMe, --CH.sub.2CH.sub.2OEt;
--CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2NMe.sub.2,
--CH.sub.2CH.sub.2N(iPr).sub.2; --CH.sub.2-Ph; (8)-Ph, -Ph-Me,
-Ph-OH, -Ph-OMe, -Ph-F, -Ph-Cl, -Ph-Br, -Ph-I; (9) --SO.sub.2Me,
--SO.sub.2Et, --SO.sub.2Ph; (10) --SO.sub.2NH.sub.2,
--SO.sub.2NMe.sub.2, --SO.sub.2NEt.sub.2; (11) --NMe.sub.2,
--NEt.sub.2; (12) morpholino; (13) --NO.sub.2; (14) --CN.
167. A compound according to claim 80, selected from the following
compounds, and pharmaceutically acceptable salts, solvates, amides,
esters, ethers, chemically protected forms, and prodrugs thereof:
187188189190191192193194195196197
168. A composition comprising a compound according to claim 80 and
a pharmaceutically acceptable carrier.
169. A method inhibiting HDAC in a cell comprising said cell with
an effective amount of a compound according to claim 80.
170. A method for the treatment of a condition mediated by HDAC
comprising administering to a subject suffering from a condition
mediated by HDAC a therapeutically-effective amount of a compound
according to claim 80.
171. A method for the treatment of a proliferative condition
comprising administering to a subject suffering from a
proliferative condition a therapeutically-effective amount of a
compound according to claim 80.
172. A method for the treatment of cancer comprising administering
to a subject suffering from cancer a therapeutically-effective
amount of a compound according to claim 80.
173. A method for the treatment of psoriasis comprising
administering to a subject suffering from psoriasis a
therapeutically-effective amount of a compound according to claim
80.
Description
RELATED APPLICATIONS
[0001] This application is related to (and where permitted by law,
claims priority to) U.S. Provisional Application No. 60/369,337
filed 3 Apr. 2002, the contents of which are incorporated herein by
reference in their entirety.
TECHNICAL FIELD
[0002] This invention pertains generally to the field of
biologically active compounds, and more specifically to certain
carbamic acid compounds which inhibit HDAC (histone deacetylase)
activity. The present invention also pertains to pharmaceutical
compositions comprising such compounds, and the use of such
compounds and compositions, both in vitro and in vivo, to inhibit
HDAC, and in the treatment of conditions mediated by HDAC, cancer,
proliferative conditions, psoriasis, etc.
BACKGROUND
[0003] Throughout this specification, including any claims which
follow, unless the context requires otherwise, the word "comprise,"
and variations such as "comprises" and "comprising," will be
understood to imply the inclusion of a stated integer or step or
group of integers or steps, but not the exclusion of any other
integer or step or group of integers or steps.
[0004] It must be noted that, as used in the specification and any
appended claims, the singular forms "a," "an," and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference, to "a pharmaceutical carrier"
includes mixtures of two or more such carriers, and the like.
[0005] Ranges are often expressed herein as from "about" one
particular value, and/or to "about" another particular value. When
such a range is expressed, another embodiment includes from the one
particular value and/or to the other particular value. Similarly,
when values are expressed as approximations, by the use of the
antecedent "about," it will be understood that the particular value
forms another embodiment.
[0006] DNA in eukaryotic cells is tightly complexed with proteins
(histones) to form chromatin. Histones are small, positively
charged proteins which are rich in basic amino acids (positively
charged at physiological pH), which contact the phosphate groups
(negatively charged at physiological pH) of DNA. There are five
main classes of histones, H1, H2A, H2B, H3, and H4. The amino acid
sequences of histones H2A, H2B, H3, and H4 show remarkable
conservation between species, whereas H1 varies somewhat, and in
some cases is replaced by another histone, e.g., H5. Four pairs of
each of H2A, H2B, H3, and H4 together form a disk-shaped octomeric
protein core, around which DNA (about 140 base pairs) is wound to
form a nucleosome. Individual nucleosomes are connected by short
stretches of linker DNA associated with another histone molecule
(e.g., H1, or in certain cases, H5) to form a structure resembling
a beaded string, which is itself arranged in a helical stack, known
as a solenoid.
[0007] The majority of histones are synthesised during the S phase
of the cell cycle, and newly synthesised histones quickly enter the
nucleus to become associated with DNA. Within minutes of its
synthesis, new DNA becomes associated with histones in nucleosomal
structures.
[0008] A small fraction of histones, more specifically, the amino
side chains thereof, are enzymatically modified by
post-translational addition of methyl, acetyl, or phosphate groups,
neutralising the positive charge of the side chain, or converting
it to a negative charge. For example, lysine and arginine groups
may be methylated, lysine groups may be acetylated, and serine
groups may be phosphorylated. For lysine, the
--(CH.sub.2).sub.4--NH.sub.2 sidechain may be acetylated, for
example by an acetyltransferase enzyme, to give the amide
--(CH.sub.2).sub.4--NHC(.d- bd.O)CH.sub.3. Methylation,
acetylation, and phosphorylation of amino termini of histones which
extend from the nucleosomal core affects chromatin structure and
gene expression. (See, for example, Spencer and Davie, 1999).
[0009] Acetylation and deacetylation of histones is associated with
transcriptional events leading to cell proliferation and/or
differentiation. Regulation of the function of transcription
factors is also mediated through acetylation. Recent reviews of
histone deacetylation include Kouzarides, 1999 and Pazin et al.,
1997.
[0010] The correlation between the acetylation status of histones
and the transcription of genes has been known for over 30 years
(see, for example, Howe et al., 1999). Certain enzymes,
specifically acetylases (e.g., histone acetyltransferase, HAT) and
deacetylases (e.g., histone deacetylase, HDAC), which regulate the
acetylation state of histones have been identified in many
organisms and have been implicated in the regulation of numerous
genes, confirming the link between acetylation and transcription.
See, for example, Davie, 1998. In general, histone acetylation
correlates with transcriptional activation, whereas histone
deacetylation is associated with gene repression.
[0011] A growing number of histone deacetylases (HDACs) have been
identified (see, for example, Ng and Bird, 2000). The first
deacetylase, HDAC1, was identified in 1996 (see, for example,
Tauton et al., 1996). Subsequently, two other nuclear mammalian
deacetylases were found, HDAC2 and HDAC3 (see, for example, Yang et
al., 1996, 1997, and Emiliani et al., 1998). See also, Grozinger et
al., 1999; Kao et al., 2000; and Van den Wyngaert et al., 2000.
[0012] Eleven (11) human HDACs have been cloned so far:
[0013] HDAC1 (Genbank Accession No. NP.sub.--004955)
[0014] HDAC2 (Genbank Accession No. NP.sub.--001518)
[0015] HDAC3 (Genbank Accession No. O15379)
[0016] HDAC4 (Genbank Accession No. MD29046)
[0017] HDAC5 (Genbank Accession No. NP.sub.--005465)
[0018] HDAC6 (Genbank Accession No. NP.sub.--006035)
[0019] HDAC7 (Genbank Accession No. AAF63491)
[0020] HDAC8 (Genbank Accession No. AAF73428)
[0021] HDAC9 (Genbank Accession No. AAK66821)
[0022] HDAC10 (Genbank Accession No. AAK84023)
[0023] HDAC11 (Genbank Accession No. NM.sub.--024827
[0024] These eleven human HDACs fall in two distinct classes: HDACs
1, 2, 3 and 8 are in class I, and HDACs 4, 5, 6, 7, 9, 10 and 11
are in class II.
[0025] There are a number of histone deacetylases in yeast,
including the following:
[0026] RPD3 (Genbank Accession No. NP.sub.--014069)
[0027] HDA1 (Genbank Accession No. P53973)
[0028] HOS1 (Genbank Accession No. Q12214)
[0029] HOS2 (Genbank Accession No. P53096)
[0030] HOS3 (Genbank Accession No. Q02959)
[0031] There are also numerous plant deacetylases, for example,
HD2, in Zea mays (Genbank Accession No. AF254073.sub.--1).
[0032] HDACs function as part of large multiprotein complexes,
which are tethered to the promoter and repress transcription. Well
characterised transcriptional repressors such as Mad (Laherty et
al., 1997), pRb (Brehm et al., 1998), nuclear receptors (Wong et
al., 1998) and YY1 (Yang et al., 1997) associate with HDAC
complexes to exert their repressor function.
[0033] The study of inhibitors of histone deacetylases indicates
that these enzymes play an important role in cell proliferation and
differentiation. The inhibitor Trichostatin A (TSA) (Yoshida et
al., 1990a) causes cell cycle arrest at both G1 and G2 phases
(Yoshida and Beppu, 1988), reverts the transformed phenotype of
different cell lines, and induces differentiation of Friend
leukaemia cells and others (Yoshida et al., 1990b). TSA (and SAHA)
have been reported to inhibit cell growth, induce terminal
differentiation, and prevent the formation of tumours in mice
(Finnin et al., 1999). 2
[0034] Cell cycle arrest by TSA correlates with an increased
expression of gelsolin (Hoshikawa et al., 1994), an actin
regulatory protein that is down regulated in malignant breast
cancer (Mielnicki et al., 1999). Similar effects on cell cycle and
differentiation have been observed with a number of deacetylase
inhibitors (Kim et al., 1999).
[0035] Trichostatin A has also been reported to be useful in the
treatment of fibrosis, e.g., liver fibrosis and liver cirrhosis.
See, e.g., Geerts et al., 1998.
[0036] Recently, certain compounds that induce differentiation have
been reported to inhibit histone deacetylases. Several experimental
antitumour compounds, such as trichostatin A (TSA), trapoxin,
suberoylanilide hydroxamic acid (SAHA), and phenylbutyrate have
been reported to act, at least in part, by inhibiting histone
deacetylase (see, e.g., Yoshida et al., 1990; Richon et al., 1998;
Kijima et al., 1993). Additionally, diallyl sulfide and related
molecules (see, e.g., Lea et al., 1999), oxamflatin (see, e.g., Kim
et al., 1999; Sonoda et al., 1996), MS-27-275, a synthetic
benzamide derivative (see, e.g., Saito et al., 1999; Suzuki et al.,
1999; note that MS-27-275 was later re-named as MS-275), butyrate
derivatives (see, e.g., Lea and Tulsyan, 1995), FR901228 (see,
e.g., Nokajima et al., 1998), depudecin (see, e.g., Kwon et al.,
1998), and m-carboxycinnamic acid bishydroxamide (see, e.g., Richon
et al., 1998) have been reported to inhibit histone deacetylases.
In vitro, some of these compounds are reported to inhibit the
growth of fibroblast cells by causing cell cycle arrest in the G1
and G2 phases, and can lead to the terminal differentiation and
loss of transforming potential of a variety of transformed cell
lines (see, e.g., Richon et al., 1996; Kim et al., 1999; Yoshida et
al., 1995; Yoshida & Beppu, 1988). In vivo, phenybutyrate is
reported to be effective in the treatment of acute promyelocytic
leukemia in conjunction with retinoic acid (see, e.g., Warrell et
al., 1998). SAHA is reported to be effective in preventing the
formation of mammary tumours in rats, and lung tumours in mice
(see, e.g., Desai et al., 1999).
[0037] The clear involvement of HDACs in the control of cell
proliferation and differentiation suggests that aberrant HDAC
activity may play a role in cancer. The most direct demonstration
that deacetylases contribute to cancer development comes from the
analysis of different acute promyelocytic leukemias (APL). In most
APL patients, a translocation of chromosomes 15 and 17 (t(15;17))
results in the expression of a fusion protein containing the
N-terminal portion of PML gene product linked to most of RAR.alpha.
(retinoic acid receptor). In some cases, a different translocation
(t(11;17)) causes the fusion between the zinc finger protein PLZF
and RAR.alpha.. In the absence of ligand, the wild type RAR.alpha.
represses target genes by tethering HDAC repressor complexes to the
promoter DNA. During normal hematopoiesis, retinoic acid (RA) binds
RAR.alpha. and displaces the repressor complex, allowing expression
of genes implicated in myeloid differentiation. The RAR.alpha.
fusion proteins occurring in APL patients are no longer responsive
to physiological levels of RA and they interfere with the
expression of the RA-inducible genes that promote myeloid
differentiation. This results in a clonal expansion of
promyelocytic cells and development of leukaemia. In vitro
experiments have shown that TSA is capable of restoring
RA-responsiveness to the fusion RAR.alpha. proteins and of allowing
myeloid differentiation. These results establish a link between
HDACs and oncogenesis and suggest that HDACs are potential targets
for pharmaceutical intervention in APL patients. (See, for example,
Kitamura et al., 2000; David et al., 1998; Lin et al., 1998).
[0038] Furthermore, different lines of evidence suggest that HDACs
may be important therapeutic targets in other types of cancer. Cell
lines derived from many different cancers (prostate, colorectal,
breast, neuronal, hepatic) are induced to differentiate by HDAC
inhibitors (Yoshida and Horinouchi, 1999). A number of HDAC
inhibitors have been studied in animal models of cancer. They
reduce tumour growth and prolong the lifespan of mice bearing
different types of transplanted tumours, including melanoma,
leukaemia, colon, lung and gastric carcinomas, etc. (Ueda et al.,
1994; Kim et al., 1999).
[0039] Psoriasis is a common chronic disfiguring skin disease which
is characterised by well-demarcated, red, hardened scaly plaques:
these may be limited or widespread. The prevalence rate of
psoriasis is approximately-2%, i.e., 12.5 million sufferers in the
triad countries (US/Europe/Japan). While the disease is rarely
fatal, it clearly has serious detrimental effects upon the quality
of life of the patient: this is further compounded by the lack of
effective therapies. Present treatments are either ineffective,
cosmetically unacceptable, or possess undesired side effects. There
is therefore a large unmet clinical need for effective and safe
drugs for this condition.
[0040] Psoriasis is a disease of complex etiology. Whilst there is
clearly a genetic component, with a number of gene loci being
involved, there are also undefined environmental triggers. Whatever
the ultimate cause of psoriasis, at the cellular level, it is
characterised by local T-cell mediated inflammation, by
keratinocyte hyperproliferation, and by localised angiogenesis.
These are all processes in which histone deacetylases have been
implicated (see, e.g., Saunders et al., 1999; Bemhard et al., 1999;
Takahashi et al., 1996; Kim et al, 2001). Therefore HDAC inhibitors
may be of use in therapy for psoriasis. Candidate drugs may be
screened, for example, using proliferation assays with T-cells
and/or keratinocytes.
[0041] Thus, one aim of the present invention is the provision of
compounds which are potent inhibitors of histone deacetylases
(HDACs). There is a pressing need for such compounds, particularly
for use as antiproliferatives, for example, anti-cancer agents,
agents for the treatment of psoriasis, etc.
[0042] Such molecules desirably have one or more of the following
properties and/or effects:
[0043] (a) easily gain access to and act upon tumour cells;
[0044] (b) down-regulate HDAC activity;
[0045] (c) inhibit the formation of HDAC complexes;
[0046] (d) inhibit the interactions of HDAC complexes;
[0047] (e) inhibit tumour cell proliferation;
[0048] (e) promote tumour cell apoptosis;
[0049] (f) inhibit tumour growth; and,
[0050] (g) complement the activity of traditional chemotherapeutic
agents.
[0051] A number of carbamic acid compounds have been described.
[0052] Certain classes of carbamic acid compounds which inhibit
HDAC are described in Watkins et al., 2002a, 2002b, and 2002c.
[0053] piperazino Amides
[0054] Alpegiani et al., 1999, describe compounds of the following
type (Q.sup.2 has backbone=2; is alkylene; is .alpha.-substituted)
which are proposed to be useful in the treatment of diseases
involving matrix metalloproteases (MMPs) and/or tumor necrosis
factor .alpha. (TNF-.alpha.). 3
[0055] Alpegiani et al., 1999, also describes the following
compound (Q.sup.2 has backbone=2; is alkylene; is
.alpha.-substituted): 4
[0056] Billedeau et al., 2000, describe compounds of the following
type (wherein R.sup.1 is, e.g., phenyl) (Q.sup.2 has backbone=3; is
alkylene; is .alpha.-substituted), which apparently inhibit
procollagen C-proteinase, and are proposed for use in the treatment
of fibrotic diseases. 5
[0057] Broadhurst et al., 1993, describe the following compound
(Q.sup.2 has backbone=2; is alkylene; is .alpha.-substituted),
which apparently inhibits collagenase. 6
[0058] Broadhurst et al., 1995, describe the following compound
(Q.sup.2 has backbone=2; is alkylene; is .alpha.-substituted),
which apparently inhibits collagenase, and is proposed for use in
the treatment of cancer, arteriosclerosis and inflammation. 7
[0059] Hou et al., 2001, describe the following compound (Q.sup.2
has backbone=2; is alkylene; is .alpha.-substituted), which
apparently inhibits the proteinase gelatinase-A. 8
[0060] Owen et al., 2001, describe the following compound (Q.sup.2
has backbone=2; is alkylene), which apparently inhibits certain
MMPS, and is proposed for use in the treatment of inflammation.
9
[0061] Pratt et al., 2001, describe the following compounds
(Q.sup.2 has backbone=2; is alkylene), which apparently have
anti-bacterial activity. 10
[0062] Piperazino Bisamides
[0063] A number of hydroxamic acids comprising a piperazine moiety
with carbonyl groups adjacent to each nitrogen atom of the
piperazine moiety are known.
[0064] Chong et al., 2002 describe the following compound (Q.sup.2
has backbone=2; is alkylene) as an inhibitor of peptide deformylase
for use as an antibiotic. 11
[0065] Billedeau et al., 2000 describe the following two compounds
(Q.sup.2 has backbone=3; is alkylene; is .alpha.-substituted) as
inhibitors of procollagen C-proteinase for use in the treatment of
fibrosis, sclerosis, arthritis and acute respiratory distress
syndrome. 12
[0066] Piperazino Sulfonamides
[0067] Barlaam et al., 2000, describe compounds of the following
type (wherein R.sup.3 may be, e.g., phenyl) (Q.sup.2 has
backbone=2; is alkylene; is optionally .beta.-substituted), which
apparently inhibit MMP-13. 13
[0068] Two examples of such compounds (Q.sup.7 has backbone=2; is
alkylene) include the following. 14
[0069] Barlaam et al., 2001, describe compounds of the following
type (Q.sup.2 has backbone=2; is alkylene) which apparently inhibit
MMP-13 and collagenase 3. 15
[0070] Barta et al., 2000, describe the following compound (Q.sup.2
has backbone=2; is phenylene), which apparently inhibits MMP-2 and
MMP-13. 16
[0071] Baxter et al., 1999, (Darwin Discovery, UK) describe the
following compound (Q.sup.2 has backbone=2; is alkylene), which
apparently inhibits certain MMPs. 17
[0072] Baxter et al., 2000, (Darwin Discovery, UK) describe
compounds of the following type (Q.sup.2 has backbone=2; is
alkylene), which apparently inhibitor certain MMPs. 18
[0073] Bedell et al., 2000, and Bedell et al., 2001, describe
compounds of the following type (Q.sup.2 has backbone=2; is
phenylene), which apparently inhibit certain MMPs. 19
[0074] De Crescenzo et al., 2000, describe compounds of the
following type (Q.sup.2 has backbone=2; is alkylene), which
apparently inhibit certain MMPs. 20
[0075] Hannah et al., 2001, (Darwin Discovery, UK) describe
compounds of the following type (Q.sup.2 has backbone=2; is
alkylene; is optionally .alpha.-substituted), which apparently
inhibit certain MMPs. 21
[0076] Martin et al., 2000, describes the following compound
(Q.sup.2 has backbone=2; is alkylene), which apparently inhibits
certain MMPs. 22
[0077] Owen et al., 2000, (Darwin Discovery, UK) describe compounds
of the following type (Q.sup.2 has backbone=2; is phenylene), which
are apparently inhibit certain MMPs. 23
[0078] Owen et al., 2000, (Darwin Discovery, UK) also describes the
following compound (Q.sup.2 has backbone=3; is phenylene): 24
SUMMARY OF THE INVENTION
[0079] One aspect of the invention pertains to active carbamic acid
compounds, as described herein.
[0080] Another aspect of the invention pertains to active
compounds, as described herein, which inhibit HDAC activity.
[0081] Another aspect of the invention pertains to active
compounds, as described herein, which treat conditions which are
known to be mediated by HDAC, or which are known to be treated by
HDAC inhibitors (such as, e.g., trichostatin A).
[0082] Another aspect of the invention pertains to active
compounds, as described herein, which (a) regulate (e.g., inhibit)
cell proliferation; (b) inhibit cell cycle progression; (c) promote
apoptosis; or (d) a combination of one or more of these.
[0083] Another aspect of the invention pertains to active
compounds, as described herein, which are anti-HDAC agents, and
which treat a condition mediated by HDAC.
[0084] Another aspect of the invention pertains to active
compounds, as described herein, which are anticancer agents, and
which treat cancer.
[0085] Another aspect of the invention pertains to active
compounds, as described herein, which are antiproliferative agents,
and which treat a proliferative condition.
[0086] Another aspect of the invention pertains to active
compounds, as described herein, which are antipsoriasis agents, and
which treat psoriasis.
[0087] Another aspect of the present invention pertains to a
composition comprising a compound, as described herein, and a
carrier.
[0088] Another aspect of the present invention pertains to a
composition comprising a compound, as described herein, and a
pharmaceutically acceptable carrier.
[0089] Another aspect of the present invention pertains to methods
of inhibiting HDAC in a cell, comprising contacting said cell with
an effective amount of an active compound, as described herein,
whether in vitro or in vivo.
[0090] Another aspect of the present invention pertains to methods
of (a) regulating (e.g., inhibiting) cell proliferation; (b)
inhibiting cell cycle progression; (c) promoting apoptosis; or (d)
a combination of one or more of these, comprising contacting a cell
with an effective amount of an active compound, as described
herein, whether in vitro or in vivo.
[0091] Another aspect of the present invention pertains to methods
of treating a condition which is known to be mediated by HDAC, or
which is known to be treated by HDAC inhibitors (such as, e.g.,
trichostatin A), comprising administering to a subject in need of
treatment a therapeutically-effective amount of an active compound,
as described herein.
[0092] Another aspect of the present invention pertains to methods
of treating cancer, comprising administering to a subject in need
of treatment a therapeutically-effective amount of an active
compound, as described herein.
[0093] Another aspect of the present invention pertains to methods
of treating a proliferative condition comprising administering to a
subject in need of treatment a therapeutically-effective amount of
an active compound, as described herein.
[0094] Another aspect of the present invention pertains to methods
of treating psoriasis comprising administering to a subject in need
of treatment a therapeutically-effective amount of an active
compound, as described herein.
[0095] Another aspect of the present invention pertains to an
active compound, as described herein, for use in a method of
treatment of the human or animal body by therapy.
[0096] Another aspect of the present invention pertains to use of
an active compound, as described herein, for the manufacture of a
medicament for use in the treatment of a condition mediated by
HDAC, a condition known to be treated by HDAC inhibitors (such as,
e.g., trichostatin A), cancer, a proliferative condition,
psoriasis, or other condition as described herein.
[0097] Another aspect of the present invention pertains to a kit
comprising (a) the active compound, preferably provided as a
pharmaceutical composition and in a suitable container and/or with
suitable packaging; and (b) instructions for use, for example,
written instructions on how to administer the active compound.
[0098] Another aspect of the present invention pertains to
compounds obtainable by a method of synthesis as described herein,
or a method comprising a method of synthesis as described
herein.
[0099] Another aspect of the present invention pertains to
compounds obtained by a method of synthesis as described herein, or
a method comprising a method of synthesis as described herein.
[0100] Another aspect of the present invention pertains to novel
intermediates, as described herein, which are suitable for use in
the methods of synthesis described herein.
[0101] Another aspect of the present invention pertains to the use
of such novel intermediates, as described herein, in the methods of
synthesis described herein.
[0102] As will be appreciated by one of skill in the art, features
and preferred embodiments of one aspect of the invention will also
pertain to other aspects of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0103] Compounds
[0104] In one aspect, the present invention pertains to carbamic
acid compounds of the formula: 25
[0105] wherein:
[0106] Cy is independently a cyclyl group;
[0107] Q.sup.1 is independently a covalent bond or cyclyl leader
group;
[0108] the piperazin-1,4-diyl group is optionally substituted;
[0109] J.sup.1 is independently a covalent bond or
--C(.dbd.O)--;
[0110] J.sup.2 is independently --C(.dbd.O) or
--S(.dbd.O).sub.2--;
[0111] Q.sup.2 is independently an acid leader group;
[0112] wherein:
[0113] Cy is independently:
[0114] C.sub.3-20carbocyclyl,
[0115] C.sub.3-20heterocyclyl, or
[0116] C.sub.5-20aryl;
[0117] and is optionally substituted;
[0118] Q.sup.1 is independently:
[0119] a covalent bond;
[0120] C.sub.1-7alkylene; or
[0121] C.sub.1-7alkylene-X--C.sub.1-7alkylene,
--X--C.sub.1-7alkylene, or C.sub.1-7alkylene-X--,
[0122] wherein X is --O-- or --S--;
[0123] and is optionally substituted;
[0124] Q.sup.2 is independently:
[0125] C.sub.4-8alkylene;
[0126] and is optionally substituted;
[0127] and has a backbone length of at least 4 atoms;
[0128] or
[0129] Q.sup.2 is independently:
[0130] C.sub.5-20arylene;
[0131] C.sub.5-20arylene-C.sub.1-7alkylene;
[0132] C.sub.1-7alkylene-C.sub.5-20arylene; or,
[0133] C.sub.1-7alkylene-C.sub.5-20arylene-C.sub.1-7alkylene;
[0134] and is optionally substituted;
[0135] and has a backbone length of at least 4 atoms;
[0136] and pharmaceutically acceptable salts, solvates, amides,
esters, ethers, chemically protected forms, and prodrugs
thereof.
[0137] In preferred embodiments, the carbamic acid group,
--C(.dbd.O)NHOH, is unmodified (e.g., is not an ester).
[0138] Note that each of the groups -J.sup.1-Q.sup.1-Cy and
-J.sup.2-Q.sup.2-C(.dbd.O)NHOH is a monovalent and monodentate
species; and that is it not intended that these groups be linked,
other than via the N-1 and N-4 atoms, respectively, of the
piperazin-1,4-diyl group.
[0139] The Piperazin-1.4-diyl Group
[0140] The piperazin-1,4-diyl group is optionally substituted,
i.e., unsubstituted or substituted.
[0141] In one embodiment, the piperazin-1,4-diyl group is
unsubstituted (i.e., unsubstituted at the 2-, 3-, 5-, and
6-positions).
[0142] In one embodiment, the piperazin-1,4-diyl group is
substituted (i.e., substituted at one or more the 2-, 3-, 5-, and
6-positions.
[0143] For example, in one embodiment, the piperazin-1,4-diyl group
is substituted
[0144] (i.e., substituted at one or more the 2-, 3-, 5-, and
6-positions with C.sub.1-4alkyl, for example, -Me or -Et.
[0145] For example, in one embodiment, the piperazin-1,4-diyl group
is:
[0146] unsubstituted piperazin-1,4-diyl or
2-methyl-piperazin-1,4-diyl.
[0147] The piperazin-1,4-diyl group may be in any conformation,
including, but not limited to, chair-, boat-, or twist-forms.
[0148] The Linkers, J.sup.1 and J.sup.2
[0149] In one embodiment, J.sup.1 is independently a covalent
bond.
[0150] In one embodiment, J.sup.1 is independently
--C(.dbd.O)--.
[0151] In one embodiment, J.sup.2 is independently
--C(.dbd.O)--.
[0152] In one embodiment, J.sup.2 is independently
--S(.dbd.O).sub.2--.
[0153] In one embodiment:
[0154] J.sup.1 is a covalent bond and J.sup.2 is --C(.dbd.O)--;
or
[0155] J.sup.1 is --C(.dbd.O)-- and J.sup.2 is --C(.dbd.O)--;
or
[0156] J.sup.1 is a covalent bond and J.sup.2 is
--S(.dbd.O).sub.2--.
[0157] In one embodiment:
[0158] J.sup.1 is a covalent bond and J.sup.2 is --C(.dbd.O)--;
or
[0159] J.sup.1 is --C(.dbd.O)-- and J.sup.2 is --C(.dbd.O)--.
[0160] In one embodiment, J.sup.1 is a covalent bond and J.sup.2 is
--C(.dbd.O)-- (and the compounds may be referred to as
"piperazino-amides"): 26
[0161] In one embodiment, J.sup.1 is --C(.dbd.O)-- and J.sup.2 is
--C(.dbd.O)-- (and the compounds may be referred to as
"piperazino-bisamides"): 27
[0162] In one embodiment, J.sup.1 is a covalent bond and J.sup.2 is
--S(.dbd.O).sub.2-- (and the compounds may be referred to as
"piperazino-sulfonamides"): 28
[0163] In one embodiment, J.sup.1 is --C(.dbd.O)-- and J.sup.2 is
--S(.dbd.O).sub.2-- (and the compounds may be referred to as
"piperazino-amide-sulfonamides"): 29
[0164] For the avoidance of doubt, it is intended that, if there is
a --C(.dbd.O)-- group immediately adjacent to the N-1 atom of the
piperazin-1-4-diyl group, then that --C(.dbd.O)-- group must be
assigned as J.sup.1 (that is, J.sup.1 is --(C.dbd.O)--) and not as
part of Q.sup.1 (e.g., as part of an oxo-substituted Q.sup.1
group). For example, if the Cy-Q.sup.1-J.sup.1- group is
Ph-CH.sub.2--C(.dbd.O)--, then Cy is Ph-, Q.sup.1 is --CH.sub.2--,
and J.sup.1 is --C(.dbd.O)--.
[0165] Assigning the Cyclyl Group, Cy
[0166] If, within the group -J.sup.1-Q.sup.1-Cy, there is a
plurality of candidate groups satisfying the definition of Cy
(referred to as candidate Cy groups), then the candidate Cy group
which is furthest from from the N-1 atom of the piperazin-1,4-diyl
group is identified as Cy (and referred to as "the relevant Cy
group").
[0167] In this context, distance (e.g., further, furthest) is
measured as the number of chain atoms in the shortest continuous
chain linking the groups (i.e., the N-1 atom and Cy).
[0168] If there is a plurality of furthest candidate Cy groups,
then the one (including any substituents) with the largest
molecular weight is the relevant one.
[0169] If there is a plurality of furthest heaviest candidate Cy
groups, then the one (excluding any substituents) with the most
annular heteroatoms is the relevant one.
[0170] If there is a plurality of furthest heaviest candidate Cy
groups with the most annular heteroatoms, then the one with an
IUPAC name which alphabetically precedes the other(s), is the
relevant one.
[0171] Some illustrative examples are shown below. 30
[0172] If the group, Q.sup.1, is a cyclyl leader group (i.e., not a
covalent bond) and/or J.sup.1 is --C(.dbd.O)--, the group
-Q.sup.1-J.sup.1- has a backbone length, as determined by the
number of chain atoms in the shortest continuous chain of atoms
linking the relevant cyclyl group, Cy, and the N-1 atom of the
piperazin-1,4-diyl group. In the following example,
-Q.sup.1-J.sup.1- has a backbone length of 2. 31
[0173] The Cyclyl Group, Cy
[0174] Cy is independently: C.sub.3-20carbocyclyl,
C.sub.3-20heterocyclyl, or C.sub.5-20aryl; and is optionally
substituted.
[0175] In one embodiment, Cy is independently
C.sub.3-20carbocyclyl; and is optionally substituted.
[0176] In one embodiment, Cy is independently monocyclic
C.sub.3-7carbocyclyl, and is optionally substituted.
[0177] In one embodiment, Cy is independently monocyclic
C.sub.5-6carbocyclyl, and is optionally substituted.
[0178] In one embodiment, Cy is independently C.sub.3-20carbocyclyl
derived from one of the following: cyclopropane, cyclobutane,
cyclopentane, cyclohexane, cyclopentene, cyclohexene, norbornane,
adamantane, cyclopentanone, and cyclohexanone; and is optionally
substituted.
[0179] In one embodiment, Cy is independently
C.sub.3-20heterocyclyl; and is optionally substituted.
[0180] In one embodiment, Cy is independently monocyclic
C.sub.3-7heterocyclyl, and is optionally substituted.
[0181] In one embodiment, Cy is independently monocyclic
C.sub.5-6heterocyclyl, and is optionally substituted.
[0182] In one embodiment, Cy is independently
C.sub.3-20heterocyclyl derived from one of the following:
piperidine, azepine, tetrahydropyran, morpholine, azetidine,
piperazine, imidazoline, piperazinedione, and oxazolinone; and is
optionally substituted.
[0183] In one embodiment, Cy is independently C.sub.5-20aryl; and
is optionally substituted.
[0184] In one embodiment, Cy is independently C.sub.5-20carboaryl
or C.sub.5-20heteroaryl; and is optionally substituted.
[0185] In one embodiment, Cy is independently C.sub.5-20heteroaryl;
and is optionally substituted. In one embodiment, Cy is monocyclic
C.sub.5-20heteroaryl; and is optionally substituted. In one
embodiment, Cy is monocyclic C.sub.5-6heteroaryl; and is optionally
substituted.
[0186] In one embodiment, Cy is independently C.sub.5-20carboaryl;
and is optionally substituted. In one embodiment, Cy is monocyclic
C.sub.5-20carboaryl; and is optionally substituted. In one
embodiment, Cy is monocyclic C.sub.5-6carboaryl; and is optionally
substituted. In one embodiment, Cy is phenyl; and is optionally
substituted.
[0187] In one embodiment, Cy is independently C.sub.5-20aryl
derived from one of the following: benzene, pyridine, furan,
indole, pyrrole, imidazole, pyrimidine, pyrazine, pyridizine,
naphthalene, quinoline, indole, benzimidazole, benzothiofuran,
fluorene, acridine, and carbazole; and is optionally
substituted.
[0188] Examples of substituents on Cy include, but are not limited
to, those described under the heading "Substituents" below.
[0189] In one embodiment, the optional substituents on Cy are as
defined under the heading "The Cyclyl Group, Cy. Optionally
Substituted Phenyl: Substituents."
[0190] The Cyclyl Group, Cy: Optionally Substituted Phenyl
[0191] In one embodiment, Cy is independently an optionally
substituted phenyl group.
[0192] In one embodiment, Cy is independently an optionally
substituted phenyl group of the formula: 32
[0193] wherein n is independently an integer from 0 to 5, and each
R.sup.A is independently a substituent as defined herein.
[0194] In one embodiment, Cy is an optionally substituted phenyl
group, Q.sup.1 is a covalent bond or a cyclyl leader group, J.sup.1
is a covalent bond, and the compounds have the following formula:
33
[0195] In one embodiment, Cy is an optionally substituted phenyl
group, Q.sup.1 is a cyclyl leader group, J.sup.1 is a covalent
bond, and the compounds have the following formula: 34
[0196] In one embodiment, Cy is an optionally substituted phenyl
group, Q.sup.1 is a covalent bond, J.sup.1 is a covalent bond, and
the compounds have the following formula: 35
[0197] In one embodiment, n is an integer from 0 to 5.
[0198] In one embodiment, n is an integer from 0 to 4.
[0199] In one embodiment, n is an integer from 0 to 3.
[0200] In one embodiment, n is an integer from 0 to 2.
[0201] In one embodiment, n is 0 or 1.
[0202] In one embodiment, n is an integer from 1 to 5.
[0203] In one embodiment, n is an integer from 1 to 4.
[0204] In one embodiment, n is an integer from 1 to 3.
[0205] In one embodiment, n is 1 or 2.
[0206] In one embodiment, n is 5.
[0207] In one embodiment, n is 4.
[0208] In one embodiment, n is 3.
[0209] In one embodiment, n is 2.
[0210] In one embodiment, n is 1.
[0211] In one embodiment, n is 0.
[0212] If the phenyl group has less than the full complement of
ring substituents, R.sup.A, they may be arranged in any
combination. For example, if n is 1, R.sup.A may be in the 2'-,
3'-, 4'-, 5'-, or 6'-position. Similarly, if n is 2, the two
R.sup.A groups may be in, for example, the 2',3'-, 2',4'-, 2',5'-,
2',6'-, 3',4'-, or 3',5'-positions. If n is 3, the three R.sup.A
groups may be in, for example, the 2',3',4'-, 2',3',5'-, 2',3',6'-,
or 3',4',5'-positions.
[0213] In one embodiment, n is 0.
[0214] In one embodiment, n is 1, and the R.sup.A group is in the
4'-position.
[0215] In one embodiment, n is 2, and one R.sup.A group is in the
4'-position, and the other R.sup.A group is in the 2'-position.
[0216] In one embodiment, n is 2, and one R.sup.A group is in the
4'-position, and the other R.sup.A group is in the 3'-position.
[0217] The Cyclyl Group, Cy: Optionally Substituted Phenyl:
Substituents
[0218] Examples of substituents on Cy (e.g., R.sup.A), include, but
are not limited to, those described under the heading
"Substituents" below.
[0219] Further examples of substituents on Cy (e.g., R.sup.A),
include, but are not limited to, those described below.
[0220] In one embodiment, each of the substituents on Cy (e.g.,
each R.sup.A), is independently selected from:
[0221] (1) ester;
[0222] (2) amido;
[0223] (3) acyl;
[0224] (4) halo;
[0225] (5) hydroxy;
[0226] (6) ether;
[0227] (7) C.sub.1-7alkyl, including substituted
C.sub.1-7alkyl;
[0228] (8) C.sub.5-20aryl, including substituted
C.sub.5-20aryl;
[0229] (9) sulfonyl;
[0230] (10) sulfonamido;
[0231] (11) amino;
[0232] (12) morpholino;
[0233] (13) nitro;
[0234] (14) cyano.
[0235] In one embodiment, each of the substituents on Cy (e.g.,
each R.sup.A), is independently selected from:
[0236] (1) --C(.dbd.O)OR.sup.1, wherein R.sup.1 is independently
C.sub.1-7alkyl as defined in (7);
[0237] (2) --C(.dbd.O)NR.sup.2R.sup.3, wherein each of R.sup.2 and
R.sup.3 is independently --H or C.sub.1-7alkyl as defined in
(7);
[0238] (3) --C(.dbd.O)R.sup.4, wherein R.sup.4 is independently
C.sub.1-7alkyl as defined in (7) or C.sub.5-20aryl as defined in
(8);
[0239] (4) --F, --Cl, --Br, --I;
[0240] (5) --OH;
[0241] (6) --OR.sup.5, wherein R.sup.5 is independently
C.sub.1-7alkyl as defined in (7) or C.sub.5-20aryl as defined in
(8);
[0242] (7) C.sub.1-7alkyl, including substituted C.sub.1-7alkyl,
e.g.,
[0243] halo-C.sub.1-7alkyl;
[0244] amino-C.sub.1-7alkyl (e.g., --(CH.sub.2).sub.w-amino);
[0245] carboxy-C.sub.1-7alkyl (e.g., --(CH.sub.2).sub.w--COOH);
[0246] hydroxy-C.sub.1-7alkyl (e.g., --(CH.sub.2).sub.w--OH);
[0247] C.sub.1-7alkoxy-C.sub.1-7alkyl (e.g.,
--(CH.sub.2).sub.w--O--C.sub.- 1-7alkyl);
[0248] C.sub.5-20aryl-C.sub.1-7alkyl;
[0249] wherein w is 1, 2, 3, or 4;
[0250] (8) C.sub.5-20aryl, including substituted
C.sub.5-20aryl;
[0251] (9) --SO.sub.2R.sup.7, wherein R.sup.7 is independently
C.sub.1-7alkyl as defined in (7) or C.sub.5-20aryl as defined in
(8);
[0252] (10) --SO.sub.2NR.sup.8R.sup.9, wherein each of R.sup.8 and
R.sup.9 is independently --H or C.sub.1-7alkyl as defined in
(7);
[0253] (11) --NR.sup.10R.sup.11, wherein each of R.sup.10 and
R.sup.11 is independently --H or C.sub.1-7 alkyl as defined in
(7);
[0254] (12) morpholino;
[0255] (13) nitro;
[0256] (14) cyano.
[0257] In one embodiment, each of the substituents on Cy (e.g.,
each R.sup.A), is independently selected from:
[0258] (1) --C(.dbd.O)OMe, --C(.dbd.O)OEt, --C(.dbd.O)O(Pr),
--C(.dbd.O)O(iPr), --C(.dbd.O)O(nBu), --C(.dbd.O)O(sBu),
--C(.dbd.O)O(iBu), --C(.dbd.O)O(tBu), --C(.dbd.O)O(nPe);
[0259] --C(.dbd.O)OCH.sub.2CH.sub.2OH,
--C(.dbd.O)OCH.sub.2CH.sub.2OMe,
--C(.dbd.O)OCH.sub.2CH.sub.2OEt;
[0260] (2) --(C.dbd.O)NH.sub.2, --(C.dbd.O)NMe.sub.2,
--(C.dbd.O)NEt.sub.2, --(C.dbd.O)N(iPr).sub.2,
--(C.dbd.O)N(CH.sub.2CH.su- b.2OH).sub.2;
[0261] (3) --(C.dbd.O)Me, --(C.dbd.O)Et, --(C.dbd.O)-Hex,
--(C.dbd.O)Ph;
[0262] (4) --F, --Cl, --Br, --I;
[0263] (5) --OH;
[0264] (6) --OMe, --OEt, --O(iPr), --O(tBu), --OPh;
[0265] --OCF.sub.3, --OCH.sub.2CF.sub.3;
[0266] --OCH.sub.2CH.sub.2OH, --OCH.sub.2CH.sub.2OMe,
--OCH.sub.2CH.sub.2OEt;
[0267] --OCH.sub.2CH.sub.2NH.sub.2, --OCH.sub.2CH.sub.2NMe.sub.2,
--OCH.sub.2CH.sub.2N(iPr).sub.2;
[0268] --OPh, --OPh-Me, --OPh-OH, --OPh-OMe, O-Ph-F, --OPh-Cl,
--OPh-Br, --OPh-I;
[0269] (7) -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, -nPe;
[0270] --CF.sub.3, --CH.sub.2CF.sub.3;
[0271] --CH.sub.2CH.sub.2OH, --CH.sub.2CH.sub.2OMe,
--CH.sub.2CH.sub.2OEt;
[0272] --CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2NMe.sub.2,
--CH.sub.2CH.sub.2N(iPr).sub.2;
[0273] --CH.sub.2-Ph;
[0274] (8) -Ph, -Ph-Me, -Ph-OH, -Ph-OMe, -Ph-F, -Ph-Cl, -Ph-Br,
-Ph-I;
[0275] (9) --SO.sub.2Me, --SO.sub.2Et, --SO.sub.2Ph;
[0276] (10) --SO.sub.2NH.sub.2, --SO.sub.2NMe.sub.2,
--SO.sub.2NEt.sub.2;
[0277] (11) --NMe.sub.2, --NEt.sub.2;
[0278] (12) morpholino;
[0279] (13) --NO.sub.2;
[0280] (14) --CN.
[0281] In one embodiment, each of the substituents on Cy (e.g.,
each R.sup.A), is independently selected from:
[0282] --C(.dbd.O)OMe, --C(.dbd.O)O(Pr), --C(.dbd.O)NHMe,
--C(.dbd.O)Et, C(.dbd.O)Ph,
[0283] --OCH.sub.2CH.sub.2OH, --OMe, --OPh,
[0284] -nPr, iPr, --CF.sub.3, --CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2NMe.sub.2,
[0285] -Ph, -Ph-F, -Ph-Cl,
[0286] --SO.sub.2Me, --SO.sub.2Me.sub.2, --NMe.sub.2,
[0287] --F, --Cl, -Me, -Et, --OMe, --OEt, --CH.sub.2-Ph,
--O--CH.sub.2-Ph.
[0288] In one embodiment, each of the substituents on Cy (e.g.,
each R.sup.A), is independently selected from:
[0289] --F, --Cl, -Me, -Et, --OMe, --OEt, -Ph, --OPh,
--CH.sub.2-Ph, --O--CH.sub.2-Ph.
[0290] Examples of some preferred substituents on Cy (e.g.,
R.sup.A), include, but are not limited to, the following: fluoro,
chloro, bromo, iodo, methyl, ethyl, isopropyl, t-butyl, cyano,
trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy,
trifluoromethoxy, phenoxy, methylthio, trifluoromethylthio,
hydroxymethyl, amino, dimethylamino, diethylamino, morpholino,
amido (unsubstituted, i.e., --CONH.sub.2), acetamido, acetyl,
nitro, sulfonamido (unsubstituted, i.e., --SO.sub.2NH.sub.2), and
phenyl.
[0291] The Cyclyl Leader Group, Q.sup.1
[0292] In one embodiment, Q.sup.1 is independently:
[0293] a covalent bond; or
[0294] a cyclyl leader group;
[0295] and is optionally substituted.
[0296] In one embodiment, Q.sup.1 is independently:
[0297] a covalent bond.
[0298] In one embodiment, Q.sup.1 is independently:
[0299] a cyclyl leader group;
[0300] and is optionally substituted.
[0301] In one embodiment, Q.sup.1 is independently:
[0302] a covalent bond;
[0303] C.sub.1-7alkylene; or
[0304] C.sub.1-7alkylene-X--C.sub.1-7alkylene,
--X--C.sub.1-7alkylene, or C.sub.1-7alkylene-X--;
[0305] wherein X is --O-- or --S--;
[0306] and is optionally substituted.
[0307] In one embodiment, Q.sup.1 is independently:
[0308] a covalent bond; or
[0309] a C.sub.1-7alkylene group;
[0310] and is optionally substituted.
[0311] In one embodiment, Q.sup.1 is independently:
[0312] a C.sub.1-7alkylene group;
[0313] and is optionally substituted.
[0314] In one embodiment, Q.sup.1 is independently:
[0315] C.sub.1-7alkylene-X--C.sub.1-7alkylene,
--X--C.sub.1-7alkylene, or C.sub.1-7alkylene-X--;
[0316] wherein X is --O-- or --S--;
[0317] and is optionally substituted.
[0318] In one embodiment, in the above alkylene groups, each
alkylene group is independently:
[0319] (a) a saturated C.sub.1-7alkylene group; or:
[0320] (b) a partially unsaturated C.sub.2-7alkylene group; or:
[0321] (c) an aliphatic C.sub.1-7alkylene group; or:
[0322] (d) a linear C.sub.1-7alkylene group; or
[0323] (e) a branched C.sub.2-7alkylene group; or:
[0324] (f) a saturated aliphatic C.sub.1-7alkylene group; or:
[0325] (g) a saturated linear C.sub.1-7alkylene group; or
[0326] (h) a saturated branched C.sub.2-7alkylene group; or
[0327] (i) a partially unsaturated aliphatic C.sub.2-7alkylene
group; or
[0328] (j) a partially unsaturated linear C.sub.2-7alkylene group;
or
[0329] (k) a partially unsaturated branched C.sub.2-7alkylene
group;
[0330] and is optionally substituted.
[0331] In one embodiment, the above alkylene groups have a maximum
number of carbon atoms of 4, e.g., C.sub.1-4alkylene,
C.sub.2-4alkylene.
[0332] In one embodiment, the above alkylene groups have a maximum
number of carbon atoms of 3, e.g., C.sub.1-3alkylene,
C.sub.2-3alkylene.
[0333] In one embodiment, Q.sup.1 is selected so that the N-1 atom
of the piperazin-1,4-diyl group is not connected to a carbon atom
which is connected to another carbon atom via a non-aromatic
carbon-carbon double bond (i.e., C.dbd.C). That is, the N-1 atom of
the piperazin-1,4-diyl group is not adjacent to a non-aromatic
carbon-carbon double bond (i.e., C.dbd.C).
[0334] In this way, groups such as --CH.dbd.CH-- and
--CH.sub.2--CH.dbd.CH-- are excluded from Q.sup.1, but groups such
as --CH.dbd.CH--CH.sub.2-- are not. Additional embodiments include
other embodiments described herein (e.g., those described above)
further limited by this restriction upon Q.sup.1.
[0335] The Cyclyl Leader Group, Q.sup.1: Covalent Bond
[0336] In one embodiment:
[0337] Q.sup.1 is independently a covalent bond;
[0338] J.sup.1 is independently a covalent bond;
[0339] J.sup.2 is independently --C(.dbd.O)--.
[0340] In one embodiment:
[0341] Q.sup.1 is independently a covalent bond;
[0342] J.sup.1 is independently --C(.dbd.O)--;
[0343] J.sup.2 is independently --C(.dbd.O)--.
[0344] In one embodiment:
[0345] Q.sup.1 is independently a covalent bond;
[0346] J.sup.1 is independently a covalent bond;
[0347] J.sup.2 is independently --S(.dbd.O).sub.2--.
[0348] In one embodiment:
[0349] Q.sup.1 is independently a covalent bond;
[0350] J.sup.1 is independently --C(.dbd.O)--;
[0351] J.sup.2 is Independently --S(.dbd.O).sub.r--.
[0352] The Cyclyl Leader Group, Q.sup.1: Backbone Length
[0353] The group -J.sup.1-Q.sup.1- has a backbone length, as
determined by the number of chain atoms in the shortest continuous
chain of atoms linking the relevant Cy group and the N-1 atom of
the piperazin-1,4-diyl group.
[0354] In one embodiment, the group -J.sup.1-Q.sup.1- has a
backbone of:
[0355] from 1 to 7 atoms;
[0356] from 1 to 6 atoms;
[0357] from 1 to 5 atoms;
[0358] from 1 to 4 atoms; or,
[0359] from 1 to 3 atoms.
[0360] In one embodiment, the group -J.sup.1-Q.sup.1- has a
backbone of at least 2 atoms. In this way, groups such as methylene
(--CH.sub.2--) and substituted methylene (--CR.sub.2-- and --CHR--)
are excluded.
[0361] In one embodiment, the group -J.sup.1-Q.sup.1- has a
backbone of at least 3 atoms.
[0362] In one embodiment, the group -J.sup.1-Q.sup.1- has a
backbone of at least 4 atoms.
[0363] In one embodiment, the group -J.sup.1-Q.sup.1- has a
backbone of at least 5 atoms.
[0364] In one embodiment, the group J.sup.1-Q.sup.1- has a backbone
of:
[0365] from 2 to 7 atoms;
[0366] from 2 to 6 atoms; or,
[0367] from 2 to 5 atoms.
[0368] In one embodiment, the group -J.sup.1-Q.sup.1- has a
backbone of:
[0369] from 3 to 7 atoms;
[0370] from 3 to 6 atoms; or,
[0371] from 3 to 5 atoms.
[0372] In one embodiment, the group -J.sup.1-Q.sup.1- has a
backbone of:
[0373] from 4 to 7 atoms;
[0374] from 4 to 6 atoms; or,
[0375] from 4 to 5 atoms.
[0376] In one embodiment, the group -J.sup.1-Q.sup.1- has a
backbone of 1 atom.
[0377] In one embodiment, the group -J.sup.1-Q.sup.1- has a
backbone of 2 atoms.
[0378] In one embodiment, the group -J.sup.1-Q.sup.1- has a
backbone of 3 atoms.
[0379] In one embodiment, the group -J.sup.1-Q.sup.1- has a
backbone of 4 atoms.
[0380] In one embodiment, the group -J.sup.1-Q.sup.1- has a
backbone of 5 atoms.
[0381] In one embodiment, the backbone of "atoms" is a backbone of
"carbon atoms."
[0382] Note that, for embodiments which are characterised by, or
further characterised by, a backbone length limitation,
corresponding changes in the description of that embodiment may be
implicit. For example, for an embodiment wherein (a) Q.sup.1 is a
partially unsaturated C.sub.2-7alkylene group and (b) Q.sup.1 has a
backbone of 4 carbon atoms, the term "C.sub.2-7alkylene" group is
necessarily, and implicitly, interpreted as
"C.sub.4-7alkylene."
[0383] The Cyclyl Leader Group, Q.sup.1: Substituents
[0384] In one embodiment, Q.sup.1, if other than a covalent bond,
is unsubstituted.
[0385] In one embodiment, Q.sup.1, if other than a covalent bond,
is optionally substituted.
[0386] In one embodiment, Q.sup.1, if other than a covalent bond,
is substituted.
[0387] Examples of substituents on Q.sup.1 include, but are not
limited to, those described under the heading "Substituents"
below.
[0388] In one embodiment, substituents on Q.sup.1, if present, are
as defined under the heading "The Cyclyl Group, Cy: Optionally
Substituted Phenyl: Substituents."
[0389] In one embodiment, substituents on Q.sup.1, if present, are
independently: halo, hydroxy, ether (e.g., C.sub.1-7alkoxy),
C.sub.5-20aryl, acyl, amino, amido, acylamido, or oxo.
[0390] In one embodiment, substituents on Q.sup.1, if present, are
independently: --F, --Cl, --Br, --I, --OH, --OMe, --OEt, --OPr,
-Ph, --NH.sub.2, --CONH.sub.2, or .dbd.O.
[0391] In one embodiment, substituents on Q.sup.1, if present, are
independently --OH or -Ph.
[0392] In one embodiment, substituents on Q.sup.1, if present, are
independently -Ph.
[0393] For example, in one embodiment, Q.sup.1 is unsubstituted
methylene, and is --CH.sub.2--; in one embodiment, Q.sup.1 phenyl
(-Ph) substituted methylene, and is --CH(Ph)-.
[0394] For example, in one embodiment, Q.sup.1 is unsubstituted
ethylene, and is --CH.sub.2--CH.sub.2--; in one embodiment, Q.sup.1
is oxo (.dbd.O) substituted ethylene, and is
--C(.dbd.O)--CH.sub.2--; in one embodiment, Q.sup.1 is hydroxy
(--OH) substituted ethylene, and is --CH(OH)--CH.sub.2--; in one
embodiment, Q.sup.1 is phenyl (-Ph) substituted ethylene, and is
--CH.sub.2CH(Ph)-.
[0395] Again, for the avoidance of doubt, it is intended that, if
there is a --C(.dbd.O)-- group immediately adjacent to the N-1 atom
of the piperazin-1-4-diyl group, then that --C(.dbd.O)--group must
be assigned as J.sup.1 (that is, J.sup.1 is --(C.dbd.O)--) and not
as part of Q.sup.1 (e.g., as part of an oxo-substituted Q.sup.1
group). For example, if the Cy-Q.sup.1-J.sup.1- group is
Ph-CH.sub.2--C(.dbd.O)--, then Cy is Ph-, Q.sup.1 is --CH.sub.2--,
and J.sup.1 is --C(.dbd.O)--.
[0396] The Cyclyl Leader Group, Q.sup.1: Alkylene: Certain
Embodiments
[0397] Note that, for embodiments excluding, e.g., a covalent bond,
certain backbone lengths, absence of adjacent carbon-carbon double
bonds, etc., it is to be understood that the corresponding species
listed below are similarly excluded from the respective embodiments
discussed below.
[0398] In one embodiment, Q.sup.1 is independently selected from
the following:
[0399] a covalent bond;
[0400] --CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, --(CH.sub.2).sub.5--, --(CH.sub.2).sub.6--,
--(CH.sub.2).sub.7;
[0401] --CH(CH.sub.3)--;
[0402] --CH(CH.sub.3)CH.sub.2--, --CH.sub.2CH(CH.sub.3)--;
[0403] --CH(CH.sub.3)CH.sub.2CH.sub.2--,
--CH.sub.2CH(CH.sub.3)CH.sub.2--,
--CH.sub.2CH.sub.2CH(CH.sub.3)--;
[0404] --CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH(CH.sub.3)CH.- sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH(CH.sub.3)CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.3)--;
[0405] --CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH(CH- .sub.3)CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.3)CH.sub.2-- -,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.3)--,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.3)--;
[0406] --CH(CH.sub.2CH.sub.3)--;
[0407] --CH(CH.sub.2CH.sub.3)CH.sub.2--,
--CH.sub.2CH(CH.sub.2CH.sub.3)--;
[0408] --CH(CH.sub.2CH.sub.3)CH.sub.2CH.sub.2--,
--CH.sub.2CH(CH.sub.2CH.s- ub.3)CH.sub.2--,
--CH.sub.2CH.sub.2CH(CH.sub.2CH.sub.3)--;
[0409] --CH(CH.sub.2CH.sub.3)CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH(CH.sub.2CH.sub.3)CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH(CH- .sub.2CH.sub.3)CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.2CH.sub.3)-- -;
[0410] --CH(CH.sub.2CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.2',
--CH.sub.2CH(CH.sub.2CH.sub.3)CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH(CH.sub.2CH.sub.3)CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.2CH.sub.3)CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.2CH.sub.3)--;
[0411] --CH.dbd.CH--;
[0412] --CH.dbd.CHCH.sub.2--, --CH.sub.2CH.dbd.CH--;
[0413] --CH.dbd.CHCH.sub.2CH.sub.2--,
--CH.sub.2CH.dbd.CHCH.sub.2--, --CH.sub.2CH.sub.2CH.dbd.CH--;
[0414] --CH.dbd.CHCH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.dbd.CHCH.sub.2C- H.sub.2--,
--CH.sub.2CH.sub.2CH.dbd.CHCH.sub.2--, --CH.sub.2CH.sub.2CH.sub-
.2CH.dbd.CH--;
[0415] --CH.dbd.CHCH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.dbd.CHCH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.dbd.C- HCH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.dbd.CHCH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.dbd.CH--;
[0416] --C(CH.sub.3).dbd.CH--, --CH.dbd.C(CH.sub.3)--;
[0417] --C(CH.sub.3).dbd.CHCH.sub.2--,
--CH.dbd.C(CH.sub.3)CH.sub.2--, --CH.dbd.CHCH(CH.sub.3)--;
[0418] --CH(CH.sub.3)CH.dbd.CH--, --CH.sub.2C(CH.sub.3).dbd.CH--,
--CH.sub.2CH.dbd.C(CH.sub.3)--;
[0419] --CH.dbd.CHCH.dbd.CH--;
[0420] --CH.dbd.CHCH.dbd.CHCH.sub.2--,
--CH.sub.2CH.dbd.CHCH.dbd.CH--, --CH.dbd.CHCH.sub.2CH.dbd.CH--;
[0421] --CH.dbd.CHCH.dbd.CHCH.sub.2CH.sub.2--,
--CH.dbd.CHCH.sub.2CH.dbd.C- HCH.sub.2--,
--CH.dbd.CHCH.sub.2CH.sub.2CH.dbd.CH--,
--CH.sub.2CH.dbd.CHCH.dbd.CHCH.sub.2--,
--CH.sub.2CH.dbd.CHCH.sub.2CH.dbd- .CH--,
--CH.sub.2CH.sub.2CH.dbd.CHCH.dbd.CH--;
[0422] --C(CH.sub.3).dbd.CHCH.dbd.CH--,
--CH.dbd.C(CH.sub.3)CH.dbd.CH--, --CH.dbd.CHC(CH.sub.3).dbd.CH--,
--CH.dbd.CHCH.dbd.C(CH.sub.3)--;
[0423] --C.ident.C--;
[0424] --C.ident.CCH.sub.2--, --CH.sub.2C.ident.C--;
--C.ident.CCH(CH.sub.3)--, --CH(CH.sub.3)C.ident.C--;
[0425] --C.ident.CCH.sub.2CH.sub.2--,
--CH.sub.2C.ident.CCH.sub.2--, --CH.sub.2CH.sub.2C.ident.C--;
[0426] --C.ident.CCH(CH.sub.3)CH.sub.2--,
--C.ident.CCH.sub.2CH(CH.sub.3)-- -;
[0427] --CH(CH.sub.3)C.ident.CCH.sub.2--,
--CH.sub.2C.ident.CCH(CH.sub.3);
[0428] --CH(CH.sub.3)CH.sub.2C.ident.C--,
--CH.sub.2CH(CH.sub.3)C.ident.C-- -;
[0429] --C.ident.CCH.dbd.CH--, --CH.dbd.CHC.ident.C--,
--C.ident.CC.ident.C--;
[0430] --C.ident.CCH.sub.2CH.sub.2CH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2C.id- ent.C--;
[0431] --C.ident.CCH.sub.2CH.sub.2CH.sub.2CH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2C.ident.C--;
[0432] --C.ident.CCH.dbd.CHCH.dbd.CH--,
--CH.dbd.CHC.ident.C--CH.dbd.CH--,
--CH.dbd.CHCH.dbd.CHC.ident.C--;
[0433] --C(CH.sub.3).dbd.CHC.ident.C--,
--CH.dbd.C(CH.sub.3)C.ident.C--, --C.ident.CC(CH.sub.3).dbd.CH--,
--C.ident.CCH.dbd.C(CH.sub.3)--.
[0434] In one embodiment, Q.sup.1 is selected from:
[0435] a covalent bond;
[0436] --CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, --(CH.sub.2).sub.5--,
--(CH.sub.2).sub.6--;
[0437] --CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.su- b.2CH(CH.sub.3)CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.3)-- -;
[0438] --CH.dbd.CH--;
[0439] --CH.dbd.CHCH.sub.2--, --CH.dbd.C(Me)CH.sub.2--;
[0440] --CH.dbd.CH--CH.dbd.CH--;
[0441] --CH.dbd.CH--CH.dbd.CHCH.sub.2--,
--CH.dbd.CHCH.sub.2CH.sub.2CH.sub- .2--,
--CH.sub.2CH.sub.2CH.sub.2CH.dbd.CH--;
[0442] --CH.dbd.CHCH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.dbd.CH--;
[0443] --C(CH.sub.3).dbd.CHCH.dbd.CH--,
--CH.dbd.C(CH.sub.3)CH.dbd.CH--, --CH.dbd.CHC(CH.sub.3).dbd.CH--,
--CH.dbd.CHCH.dbd.C(CH.sub.3)--;
[0444] In one embodiment, Q.sup.1 is selected from:
[0445] a covalent bond;
[0446] --CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, --(CH.sub.2).sub.5--,
[0447] --CH.dbd.CH--;
[0448] --CH.dbd.CHCH.sub.2--, --CH.dbd.C(Me)CH.sub.2--;
[0449] --CH.dbd.CH--CH.dbd.CH--;
[0450] --C(CH.sub.3).dbd.CHCH.dbd.CH--,
--CH.dbd.C(CH.sub.3)CH.dbd.CH--, --CH.dbd.CHC(CH.sub.3).dbd.CH--,
--CH.dbd.CHCH.dbd.C(CH.sub.3)--;
[0451] --CH.dbd.CHCH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH- .dbd.CH--.
[0452] In one embodiment, Q.sup.1 is independently selected
from:
[0453] a covalent bond;
[0454] --CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, --(CH.sub.2).sub.5--;
[0455] --CH.dbd.CHCH.sub.2--;
[0456] --CH.dbd.C(Me)CH.sub.2--; and,
[0457] --CH.dbd.CH--CH.dbd.CHCH.sub.2--.
[0458] In one embodiment, Q.sup.1 is independently selected
from:
[0459] a covalent bond;
[0460] --CH.sub.2--;
[0461] --CH.sub.2CH.sub.2--;
[0462] --CH.sub.2CH.sub.2CH.sub.2--;
[0463] --CH.dbd.CHCH.sub.2--;
[0464] --CH.dbd.C(Me)CH.sub.2--; and,
[0465] --CH.dbd.CH--CH.dbd.CHCH.sub.2--.
[0466] In one embodiment, Q.sup.1 is independently selected
from:
[0467] a covalent bond;
[0468] --CH.sub.2--;
[0469] --CH(*Ph)-;
[0470] --CH.sub.2CH.sub.2--;
[0471] --CH(*Ph)CH.sub.2--;
[0472] --CH.sub.2CH(*Ph)-;
[0473] --CH.sub.2CH.sub.2CH.sub.2--;
[0474] --CH.dbd.CHCH.sub.2--;
[0475] --CH.dbd.C(Me)CH.sub.2--; and,
[0476] --CH.dbd.CH--CH.dbd.CHCH.sub.2--;
[0477] wherein * indicates that the group (e.g., Ph) is optionally
substituted with one or more substituents as defined above under
the heading "The Cyclyl Group, Cy: Optionally Substituted Phenyl:
Substituents."
[0478] The Cyclyl Leader Group, Q.sup.1: Ethers and Thioethers:
Certain Embodiments
[0479] Note that, for embodiments excluding, e.g., a covalent bond,
certain backbone lengths, absence of adjacent carbon-carbon double
bonds, etc., it is to be understood that the corresponding species
listed below are similarly excluded from the respective embodiments
discussed below.
[0480] In one embodiment, Q.sup.1 is independently selected from
the following:
[0481] --(CH.sub.2).sub.a--X--(CH.sub.2).sub.b--
[0482] wherein X is --O-- or --S-- and
[0483] a and b are each independently 1, 2, 3, 4, 5, 6, or 7;
[0484] and a+b is at least 1.
[0485] In one embodiment, Q.sup.1 is independently selected from
the following:
[0486] --O--(CH.sub.2).sub.a--
[0487] --S--(CH.sub.2).sub.a--
[0488] --(CH.sub.2).sub.a--O--
[0489] --(CH.sub.2).sub.a--S--
[0490] --(CH.sub.2).sub.a--O--(CH.sub.2).sub.b--
[0491] --(CH.sub.2).sub.a--S--(CH.sub.2).sub.b--
[0492] wherein a and b are each independently 1, 2, 3, 4, 5, 6, or
7.
[0493] In one embodiment, Q.sup.1 is independently selected from
the following:
[0494] --O--CH.sub.2--; --O--CH.sub.2CH.sub.2--;
--O--CH.sub.2CH.sub.2CH.s- ub.2--;
[0495] --S--CH.sub.2--; --S--CH.sub.2CH.sub.2--;
--S--CH.sub.2CH.sub.2CH.s- ub.2--;
[0496] --CH.sub.2--O--; --CH.sub.2CH.sub.2--O--;
--CH.sub.2CH.sub.2CH.sub.- 2--O--;
[0497] --CH.sub.2--S--; --CH.sub.2CH.sub.2--S--;
--CH.sub.2CH.sub.2CH.sub.- 2--S--;
[0498] --CH.sub.2--O--CH.sub.2--;
--CH.sub.2--O--CH.sub.2CH.sub.2--;
--CH.sub.2CH.sub.2--O--CH.sub.2--; and
[0499] --CH.sub.2CH.sub.2--O--CH.sub.2CH.sub.2--.
[0500] The Group -Q.sup.1-J.sup.1-: Certain Embodiments
[0501] In one embodiment, the group -Q.sup.1-J.sup.1- has a formula
selected from:
[0502] --CH.sub.2--;
[0503] --CH(*Ph)-;
[0504] --CH.sub.2CH.sub.2--;
[0505] --CH.sub.2CH(*Ph)-;
[0506] --CH(*Ph)CH.sub.2--;
[0507] --CH.sub.2CH.sub.2CH.sub.2--;
[0508] --C(.dbd.O)--;
[0509] --CH.sub.2--C(.dbd.O)--;
[0510] --CH(*Ph)-C(.dbd.O)--;
[0511] --CH.sub.2CH.sub.2--C(.dbd.O)--;
[0512] --O--CH.sub.2--;
[0513] --O--CH.sub.2CH.sub.2--;
[0514] --CH.sub.2--O--;
[0515] --CH.sub.2CH.sub.2--O--; and,
[0516] --O--CH.sub.2--C(.dbd.O)--.
[0517] wherein * indicates that the group (e.g., Ph) is optionally
substituted with one or more substituents as defined above under
the heading "The Cyclyl Group, Cy: Optionally Substituted Phenyl:
Substituents."
[0518] The Group Cy-Q.sup.1-: Certain Embodiments
[0519] In one embodiment, the group Cy-Q.sup.1- has a formula
selected from:
[0520] *Ph-;
[0521] *Ph-CH.sub.2--;
[0522] (*Ph).sub.2CH--;
[0523] *Ph-CH.sub.2CH.sub.2--;
[0524] (*Ph).sub.2--CH.sub.2CH.sub.2--;
[0525] *Ph-CH.sub.2CH(*Ph);
[0526] *Ph-CH.sub.2CH.sub.2CH.sub.2--;
[0527] *Ph-CH.dbd.CHCH.sub.2--;
[0528] *Ph-CH.dbd.C(Me)CH.sub.2--;
[0529] *Ph-CH.dbd.CHCH.dbd.CHCH.sub.2--;
[0530] (*pyrid-3-yl)-CH.dbd.CHCH.sub.2--; and,
[0531] (*cyclohexyl)-CH.sub.2CH.sub.2--;
[0532] wherein * indicates that the group (e.g., Ph, pyrid-3-yl,
cyclohexyl) is optionally substituted with one or more substituents
as defined above under the heading "The Cyclyl Group, Cy:
Optionally Substituted Phenyl: Substituents."
[0533] In one embodiment, * indicates that the group (e.g., Ph,
pyrid-3-yl, cyclohexyl) is optionally substituted with one or more
of: --F, --Cl, --Br, --I, --H, --OMe, --OEt, --OPr, -Ph,
--NH.sub.2, and --CONH.sub.2.
[0534] The Acid Leader Group, Q.sup.2
[0535] The acid leader group, Q.sup.2, is independently:
[0536] C.sub.4-8alkylene;
[0537] and is optionally substituted;
[0538] and has a backbone length of at least 4 atoms;
[0539] or:
[0540] C.sub.5-20arylene;
[0541] C.sub.5-20arylene-C.sub.1-7alkylene;
[0542] C.sub.1-7alkylene-C.sub.5-20arylene; or,
[0543] C.sub.1-7alkylene-C.sub.5-20arylene-C.sub.1-7alkylene;
[0544] and is optionally substituted;
[0545] and has a backbone length of at least 4 atoms.
[0546] In one embodiment, the acid leader group, Q.sup.2, is
independently:
[0547] C.sub.4-8alkylene;
[0548] and is optionally substituted;
[0549] and has a backbone length of at least 4 atoms.
[0550] In one embodiment, the acid leader group, Q.sup.2, is
independently:
[0551] C.sub.5-20arylene;
[0552] C.sub.5-20arylene-C.sub.1-7alkylene;
[0553] C.sub.1-7alkylene-C.sub.5-20arylene;
[0554] C.sub.1-7alkylene-C.sub.5-20arylene-C.sub.1-7alkylene;
or,
[0555] and is optionally substituted;
[0556] and has a backbone length of at least 4 atoms.
[0557] The Acid Leader Group, Q.sup.2: Backbone Length
[0558] The acid leader group, Q.sup.2, has a backbone length, as
determined by the number of chain atoms in the shortest continuous
chain of atoms linking the N-4 atom of the piperazin-1,4-diyl group
and the carbamic acid group, --C(.dbd.O)NHOH.
[0559] If Q.sup.2 is alkylene, Q.sup.2 necessarily has a backbone
of at least 1 atom. Some examples are shown below. 36
[0560] If Q.sup.2 is arylene, arylene-alkylene, alkylene-arylene,
alkylene-arylene-alkylene, Q.sup.2 necessarily has a backbone of at
least 2 atoms. Some examples are shown below. 37
[0561] Without wishing to be bound to any particular theory, it is
believed that Q.sup.2 groups with shorter backbone lengths prevent
or reduce the interaction of the carbamic acid group
(--C(.dbd.O)NHOH) with HDAC (or its complexes), and thereby reduce
the compound's activity as an HDAC inhibitor.
[0562] In one embodiment, Q.sup.2 has a backbone of at least 4
atoms.
[0563] In one embodiment, Q.sup.2 has a backbone of at least 5
atoms.
[0564] In one embodiment, Q.sup.2 has a backbone of at least 6
atoms.
[0565] In one embodiment, Q.sup.2 has a backbone of:
[0566] from 4 to 8 atoms;
[0567] from 4 to 7 atoms;
[0568] from 4 to 6 atoms; or,
[0569] from 4 to 5 atoms.
[0570] In one embodiment, Q.sup.2 has a backbone of:
[0571] from 5 to 8 atoms; or
[0572] from 5 to 7 atoms; or
[0573] from 5 to 6 atoms.
[0574] In one embodiment, Q.sup.2 has a backbone of from 5 to 6
atoms.
[0575] In one embodiment, Q.sup.2 has a backbone of 4 atoms.
[0576] In one embodiment, Q.sup.2 has a backbone of 5 atoms.
[0577] In one embodiment, Q.sup.2 has a backbone of 6 atoms.
[0578] In one embodiment, Q.sup.2 has a backbone of 7 atoms.
[0579] In one embodiment, Q.sup.2 has a backbone of 8 atoms.
[0580] In one embodiment, the backbone of "atoms" is a backbone of
"carbon atoms."
[0581] Note that, for embodiments which are characterised by, or
further characterised by, a backbone length limitation,
corresponding changes in the description of that embodiment may be
implicit. For example, for an embodiment wherein (a) Q.sup.2 is a
partially unsaturated C.sub.2-8alkylene group and (b) Q.sup.2 has a
backbone of 4 carbon atoms, the term "C.sub.2-8alkylene" group is
necessarily, and implicitly, interpreted as
"C.sub.4-8alkylene."
[0582] The Acid Leader Group, Q.sup.2: Substitution
[0583] In one embodiment, Q.sup.2 is unsubstituted.
[0584] In one embodiment, Q.sup.2 is optionally substituted.
[0585] In one embodiment, Q.sup.2 is substituted.
[0586] The backbone atoms of the acid leader group, Q.sup.2, which
link J and the carbamic acid group (--C(.dbd.O)NHOH), are denoted
.alpha., .beta., .gamma., .delta., etc., starting with the backbone
atom adjacent to the carbamic acid group. Some examples are
illustrated below. 38
[0587] Without wishing to be bound to any particular theory, it is
believed that groups (e.g., substituents), particularly bulky
groups (e.g., substituents), at the .alpha.-position, or at either
or both of the .alpha.- and .beta.-positions, prevent or reduce the
interaction of the carbamic acid group (--C(.dbd.O)NHOH) with HDAC
(or its complexes), and thereby reduce the compound's activity as
an HDAC inhibitor.
[0588] In one embodiment, Q.sup.2 is, additionally, unsubstituted
at the .alpha.-position.
[0589] In one embodiment, Q.sup.2 is, additionally, unsubstituted
at the .alpha.-position and unsubstituted at the
.beta.-position.
[0590] Note that, in some embodiments, Q.sup.2 may have a
non-linear alkylene group (for example, a branched alkylene)
adjacent to the carbamic acid group. An example, wherein Q.sup.2 is
a branched saturated C.sub.6-alkylene, having a methyl group at the
.alpha.-position, is shown below. Although there is a group (i.e.,
a methyl group) at the .alpha.-position, such compounds are
unsubstituted at the .alpha.-position, because the .alpha.-methyl
group itself is considered to be part of the unsubstituted Q.sup.2.
Another example, wherein Q.sup.2 is a branched saturated
C.sub.6-alkylene, having an amino group at the .alpha.-position and
a methyl group at the .beta.-position, is shown below; such
compounds are .alpha.-substituted, .beta.-unsubstituted. 39
[0591] In one embodiment, in which Q.sup.2 is a group as defined
herein (e.g., C.sub.4-8alkylene,
C.sub.5-20arylene-C.sub.1-7alkylene,
C.sub.1-7alkylene-C.sub.5-20arylene-C.sub.1-7alkylene) having an
alkylene group adjacent to the carbamic acid group, Q.sup.2 is,
additionally, unsubstituted at the .alpha.-position.
[0592] In one embodiment, in which Q.sup.2 is a group as defined
herein (e.g., C.sub.4-8alkylene,
C.sub.5-20arylene-C.sub.1-7alkylene,
C.sub.1-7alkylene-C.sub.5-20arylene-C.sub.1-7alkylene) having an
alkylene group adjacent to the carbamic acid group, that adjacent
alkylene group has a --CH.sub.2-- or .dbd.CH-- group adjacent to
the carbamic acid group (that is, at the .alpha.-position).
[0593] In one embodiment, in which Q.sup.2 is a group as defined
herein (e.g., C.sub.4-8alkylene,
C.sub.5-20arylene-C.sub.1-7alkylene,
C.sub.1-7alkylene-C.sub.5-20arylene-C.sub.1-7alkylene) having an
alkylene group adjacent to the carbamic acid group, that adjacent
alkylene group has a --CH.sub.2-- group adjacent to the carbamic
acid group (that is, at the .alpha.-position).
[0594] In one embodiment, in which Q.sup.2 is a group as defined
herein (e.g., C.sub.4-8alkylene,
C.sub.5-20arylene-C.sub.1-7alkylene,
C.sub.1-7alkylene-C.sub.5-20arylene-C.sub.1-7alkylene) having an
alkylene group adjacent to the carbamic acid group, that adjacent
alkylene group has a .dbd.CH-- group adjacent to the carbamic acid
group (that is, at the .alpha.-position).
[0595] In one embodiment, in which Q.sup.2 is a group as defined
herein (e.g., C.sub.4-8alkylene,
C.sub.5-20arylene-C.sub.1-7alkylene,
C.sub.1-7alkylene-C.sub.5-20arylene-C.sub.1-7alkylene) having an
alkylene group adjacent to the carbamic acid group, Q.sup.2 is,
additionally, unsubstituted at the .alpha.-position and
unsubstituted at the .beta.-position.
[0596] In one embodiment, in which Q.sup.2 is a group as defined
herein (e.g., C.sub.4-8alkylene,
C.sub.5-20arylene-C.sub.1-7alkylene,
C.sub.1-7alkylene-C.sub.5-20arylene-C.sub.1-7alkylene) having an
alkylene group adjacent to the carbamic acid group, that adjacent
alkylene group has a --CH.sub.2CH.sub.2--, --CH.dbd.CH--, or
--C.ident.C-- group adjacent to the carbamic acid group (that is,
at the .alpha.,.beta.-position).
[0597] In one embodiment, in which Q.sup.2 is a group as defined
herein (e.g., C.sub.4-8alkylene,
C.sub.5-20arylene-C.sub.1-7alkylene,
C.sub.1-7alkylene-C.sub.5-20arylene-C.sub.1-7alkylene) having an
alkylene group adjacent to the carbamic acid group, that adjacent
alkylene group has a --CH.sub.2CH.sub.2-- or --CH.dbd.CH-- group
adjacent to the carbamic acid group (that is, at the
.alpha.,.beta.-position).
[0598] In one embodiment, in which Q.sup.2 is a group as defined
herein (e.g., C.sub.4-8alkylene,
C.sub.5-20arylene-C.sub.1-7alkylene,
C.sub.1-7alkylene-C.sub.5-20arylene-C.sub.1-7alkylene) having an
alkylene group adjacent to the carbamic acid group, that adjacent
alkylene group has a --CH.sub.2CH.sub.2-- group adjacent to the
carbamic acid group (that is, at the .alpha.,.beta.-position).
[0599] In one embodiment, in which Q.sup.2 is a group as defined
herein (e.g., C.sub.4-8alkylene,
C.sub.5-20arylene-C.sub.1-7alkylene,
C.sub.1-7alkylene-C.sub.5-20arylene-C.sub.1-7alkylene) having an
alkylene group adjacent to the carbamic acid group, that adjacent
alkylene group has a --CH.dbd.CH-- group adjacent to the carbamic
acid group (that is, at the .alpha.,.beta.-position).
[0600] Examples of substituents on Q.sup.2 include, but are not
limited to, those described under the heading "Substituents"
below.
[0601] In one embodiment, the optional substituents on Q.sup.2 are
as defined under the heading "The Cyclyl Group, Cy: Optionally
Substituted Phenyl: Substituents."
[0602] The Acid Leader Group, Q.sup.2: Alkylene
[0603] In one embodiment, the acid leader group, Q.sup.2, is
C.sub.4-8alkylene, and is optionally substituted, and has a
backbone length of at least 4 atoms.
[0604] In one embodiment, Q.sup.2 is independently a saturated
C.sub.4-8alkylene group.
[0605] In one embodiment, Q.sup.2 is independently a partially
unsaturated C.sub.4-8alkylene group.
[0606] In one embodiment, Q.sup.2 is independently an aliphatic
C.sub.4-8alkylene group.
[0607] In one embodiment, Q.sup.2 is independently a linear
C.sub.4-8alkylene group.
[0608] In one embodiment, Q.sup.2 is independently a branched
C.sub.4-8alkylene group.
[0609] In one embodiment, Q.sup.2 is independently an alicyclic
C.sub.4-8alkylene group.
[0610] In one embodiment, Q.sup.2 is independently a saturated
aliphatic C.sub.4-8alkylene group.
[0611] In one embodiment, Q.sup.2 is independently a saturated
linear C.sub.4-8alkylene group.
[0612] In one embodiment, Q.sup.2 is independently a saturated
branched C.sub.4-8alkylene group.
[0613] In one embodiment, Q.sup.2 is independently a saturated
alicyclic C.sub.4-8alkylene group.
[0614] In one embodiment, Q.sup.2 is independently a partially
unsaturated aliphatic C.sub.4-8alkylene group.
[0615] In one embodiment, Q.sup.2 is independently a partially
unsaturated linear C.sub.4-8alkylene group.
[0616] In one embodiment, Q.sup.2 is independently a partially
unsaturated branched C.sub.4-8alkylene group.
[0617] In one embodiment, Q.sup.2 is independently a partially
unsaturated alicyclic C.sub.4-8alkylene group.
[0618] Note that, for embodiments excluding, e.g., certain backbone
lengths, absence of adjacent carbon-carbon double bonds, etc., it
is to be understood that the corresponding species listed below are
similarly excluded from the respective embodiments discussed
below.
[0619] In one embodiment, Q.sup.2 is independently selected
from:
[0620] --(CH.sub.2).sub.4--, --(CH.sub.2).sub.5,
--(CH.sub.2).sub.6--, --(CH.sub.2).sub.7--,
--(CH.sub.2).sub.8--;
[0621] --CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH(CH.sub.3)CH.- sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH(CH.sub.3)CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.3)--;
[0622] --CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH(CH- .sub.3)CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.3)CH.sub.2-- -,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.3)--,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.3)--;
[0623] --CH(CH.sub.2CH.sub.3)CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH(CH.sub.2CH.sub.3)CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH(CH- .sub.2CH.sub.3)CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.2CH.sub.3)-- -;
[0624] --CH(CH.sub.2CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH(CH.sub.2CH.sub.3)CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH(CH.sub.2CH.sub.3)CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.2CH.sub.3)CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.2CH.sub.3)--;
[0625] --CH.dbd.CHCH.sub.2CH.sub.2--,
--CH.sub.2CH.dbd.CHCH.sub.2--, --CH.sub.2CH.sub.2CH.dbd.CH--;
--CH.dbd.CHCH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.dbd.CHCH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.dbd.CHCH.sub.- 2,
--CH.sub.2CH.sub.2CH.sub.2CH.dbd.CH--;
--CH.dbd.CHCH.sub.2CH.sub.2CH.su- b.2CH.sub.2,
--CH.sub.2CH.dbd.CHCH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.dbd.CHCH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2- CH.dbd.CHCH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.dbd.CH--;
[0626] --CH.dbd.CHCH.dbd.CH--;
[0627] --CH.dbd.CHCH.dbd.CHCH.sub.2--,
--CH.sub.2CH.dbd.CHCH.dbd.CH--, --CH.dbd.CHCH.sub.2CH.dbd.CH--;
[0628] --CH.dbd.CHCH.dbd.CHCH.sub.2CH.sub.2--,
--CH.dbd.CHCH.sub.2CH.dbd.C- HCH.sub.2,
--CH.dbd.CHCH.sub.2CH.sub.2CH.dbd.CH--, --CH.sub.2CH.dbd.CHCH.d-
bd.CHCH.sub.2--, --CH.sub.2CH.dbd.CHCH.sub.2CH.dbd.CH--,
--CH.sub.2CH.sub.2CH.dbd.CHCH.dbd.CH--;
[0629] --C(CH.sub.3).dbd.CHCH.dbd.CH--,
--CH.dbd.C(CH.sub.3)CH.dbd.CH--, --CH.dbd.CHC(CH.sub.3).dbd.CH--,
--CH.dbd.CHCH.dbd.C(CH.sub.3)--;
[0630] --C.ident.CCH.sub.2CH.sub.2--,
--CH.sub.2C.ident.CCH.sub.2--, --CH.sub.2CH.sub.2C.ident.C--;
[0631] --C.ident.CCH(CH.sub.3)CH.sub.2--,
--C.ident.CCH.sub.2CH(CH.sub.3)-- -;
[0632] --CH(CH.sub.3)C.ident.CCH.sub.2--,
--CH.sub.2C.dbd.CCH(CH.sub.3)--;
[0633] --CH(CH.sub.3)CH.sub.2C.dbd.C--,
--CH.sub.2CH(CH.sub.3)C.ident.C--;
[0634] --C.ident.CCH.dbd.CH--, --CH.dbd.CHC.dbd.C--,
--C.ident.CC.ident.C--;
[0635] --C.ident.CCH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2C.- ident.C--;
[0636] --C.ident.CCH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2C.ident.C--;
[0637] --C.ident.CCH.dbd.CHCH.dbd.CH--,
--CH.dbd.CHC.ident.C--CH.dbd.CH--,
--CH.dbd.CHCH.dbd.CHC.ident.C--;
[0638] --C(CH.sub.3).dbd.CHC.ident.C--,
--CH.dbd.C(CH.sub.3)C.ident.C--, --C.ident.CC(CH.sub.3).dbd.CH--,
--C.ident.CCH.dbd.C(CH.sub.3)--;
[0639] cyclopentylene cyclopentenylene;
[0640] cyclohexylene, cyclohexenylene, cyclohexadienylene; 40
[0641] In one preferred embodiment, Q.sup.2 is independently
selected from:
[0642] --(CH.sub.2).sub.5--;
[0643] --(CH.sub.2).sub.6--;
[0644] --(CH.sub.2).sub.7--;
[0645] --(CH.sub.2).sub.8--;
[0646] --CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.2--;
[0647] --CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.3)--;
[0648] --CH.sub.2CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.2--;
[0649] --CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.3)--;
[0650] --CH.sub.2CH.sub.2CH.sub.2CH.dbd.CH--;
[0651] --CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.dbd.CH--; 41
[0652] In one preferred embodiment, Q.sup.2 is independently
selected from:
[0653] --(CH.sub.2).sub.5--;
[0654] --(CH.sub.2).sub.6--;
[0655] --(CH.sub.2)--;
[0656] --(CH.sub.2).sub.8--;
[0657] --CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.2--;
[0658] --CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.3)--;
[0659] --CH.sub.2CH.sub.2CH.sub.2CH.dbd.CH--; and,
[0660] --CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.dbd.CH--.
[0661] In one preferred embodiment, Q.sup.2 is independently
selected from:
[0662] --(CH.sub.2).sub.5--, --(CH.sub.2).sub.6,
--(CH.sub.2).sub.7, and --(CH.sub.2).sub.8--.
[0663] The Acid Leader Group, Q.sup.2: Arylene
[0664] In one embodiment, the add leader group, Q.sup.2, is
independently:
[0665] C.sub.5-20arylene (denoted --Ar--),
[0666] and is optionally substituted,
[0667] and has a backbone length of at least 4 atoms.
[0668] In one embodiment, Q.sup.2 is C.sub.5-20arylene; and is
optionally substituted.
[0669] In one embodiment, Q.sup.2 is C.sub.5-6arylene; and is
optionally substituted.
[0670] In one embodiment, Q.sup.2 is phenylene; and is optionally
substituted.
[0671] In one embodiment, Q.sup.2 additionally has a backbone
length as described above under the heading "The Acid Leader Group,
Q.sup.2: Backbone Length."
[0672] The Acid Leader Group, Q.sup.2:
[0673] Alkylene-Arylene, Arylene-Alkylene, and
Alkylene-Arylene-Alkylene
[0674] In one preferred embodiment, the acid leader group, Q.sup.2,
is independently:
[0675] C.sub.5-20arylene-C.sub.1-7alkylene;
[0676] C.sub.1-7alkylene-C.sub.5-20arylene; or,
[0677] C.sub.1-7alkylene-C.sub.5-20arylene-C.sub.1-7alkylene;
[0678] and is optionally substituted;
[0679] and has a backbone length of at least 4 atoms.
[0680] In one preferred embodiment, the acid leader group, Q.sup.2,
is independently:
[0681] C.sub.5-20arylene-C.sub.1-7alkylene;
[0682] and is optionally substituted;
[0683] and has a backbone length of at least 4 atoms.
[0684] In one preferred embodiment, the acid leader group, Q.sup.2,
is independently:
[0685] C.sub.1-7alkylene-C.sub.5-20arylene; or,
[0686] and is optionally substituted;
[0687] and has a backbone length of at least 4 atoms.
[0688] In one preferred embodiment, the acid leader group, Q.sup.2,
is independently:
[0689] C.sub.1-7alkylene-C.sub.5-20arylene-C.sub.1-7alkylene;
[0690] and is optionally substituted;
[0691] and has a backbone length of at least 4 atoms.
[0692] In one preferred embodiment, Q.sup.2 is independently:
[0693] C.sub.5-6arylene-C.sub.1-7alkylene;
[0694] C.sub.1-7alkylene-C.sub.5-6arylene; or,
[0695] C.sub.1-7alkylene-C.sub.5-6arylene-C.sub.1-7alkylene;
[0696] and is optionally substituted;
[0697] and has a backbone length of at least 4 atoms.
[0698] In one preferred embodiment, Q.sup.2 is independently:
[0699] phenylene-C.sub.1-7alkylene;
[0700] C.sub.1-7alkylene-phenylene; or,
[0701] C.sub.1-7alkylene-phenylene-C.sub.1-7alkylene;
[0702] and is optionally substituted;
[0703] and has a backbone length of at least 4 atoms.
[0704] In one embodiment, Q.sup.2 is
C.sub.1-7alkylene-C.sub.5-20arylene; and is optionally
substituted.
[0705] In one embodiment, Q.sup.2 is
C.sub.1-7alkylene-C.sub.5-6arylene; and is optionally
substituted.
[0706] In one embodiment, Q.sup.2 is independently
C.sub.1-7alkylene-pheny- lene; and is optionally substituted.
[0707] In one embodiment, Q.sup.2 is
C.sub.5-20arylene-C.sub.1-7alkylene; and is optionally
substituted.
[0708] In one embodiment, Q.sup.2 is
C.sub.5-6arylene-C.sub.1-7alkylene; and is optionally
substituted.
[0709] In one embodiment, Q.sup.2 is independently
phenylene-C.sub.1-7alky- lene; and is optionally substituted.
[0710] In one embodiment, Q.sup.2 is
C.sub.1-7alkylene-C.sub.5-20arylene-C- .sub.1-7alkylene; and is
optionally substituted.
[0711] In one embodiment, Q.sup.2 is
C.sub.1-7alkylene-C.sub.5-6arylene-C.- sub.1-7alkylene; and is
optionally substituted.
[0712] In one embodiment, Q.sup.2 is independently
C.sub.1-7alkylene-pheny- lene-C.sub.1-7alkylene; and is optionally
substituted.
[0713] In the above arylene-alkylene (denoted --Ar--R.sup.Q22--),
alkylene-arylene (denoted --R.sup.Q21--Ar--), and
alkylene-arylene-alkyle- ne (denoted --R.sup.Q21--Ar--R.sup.Q22)
groups, each of R.sup.Q21 and R.sup.Q22 is independently
C.sub.1-7alkylene.
[0714] In one embodiment, in the above arylene-alkylene,
alkylene-arylene, and alkylene-arylene-alkylene groups, each
alkylene group is independently:
[0715] (a) a saturated C.sub.1-7alkylene group; or
[0716] (b) a partially unsaturated C.sub.2-7alkylene group; or:
[0717] (c) an aliphatic C.sub.1-7alkylene group; or:
[0718] (d) a linear C.sub.1-7alkylene group; or
[0719] (e) a branched C.sub.2-7alkylene group; or:
[0720] (f) a saturated aliphatic C.sub.1-7alkylene group; or:
[0721] (g) a saturated linear C.sub.1-7alkylene group; or
[0722] (h) a saturated branched C.sub.2-7alkylene group; or
[0723] (i) a partially unsaturated aliphatic C.sub.2-7alkylene
group; or:
[0724] (j) a partially unsaturated linear C.sub.2-7alkylene group;
or:
[0725] (k) a partially unsaturated branched C.sub.2-7alkylene
group;
[0726] and is optionally substituted.
[0727] In one embodiment, Q.sup.2 additionally has a backbone
length as described above under the heading "The Acid Leader Group,
Q.sup.2: Backbone Length."
[0728] Alkylene Groups R.sup.Q21 and R.sup.Q22: Certain
Embodiments
[0729] Note that, for embodiments excluding, e.g., certain backbone
lengths, absence of adjacent carbon-carbon double bonds, etc., it
is to be understood that the corresponding species listed below are
similarly excluded from the respective embodiments discussed
below.
[0730] In one embodiment, each of R.sup.Q21 and R.sup.Q22 is
independently as defined for Q.sup.1 under the heading "The Cyclyl
Leader Group, Q.sup.1: Alkylene: Certain Embodiments."
[0731] In one embodiment, R.sup.Q21 is independently selected
from:
[0732] --CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, --(CH.sub.2).sub.5--, --(CH.sub.2).sub.6,
[0733] --CHrCH.dbd.CH--; and,
[0734] --CH.sub.2--CH.dbd.CH--CH.dbd.CH--.
[0735] In one embodiment, R.sup.Q21 is independently selected
from:
[0736] --CH.sub.2--, --CH.sub.2CH.sub.2--, and
--CH.sub.2--CH.dbd.CH--.
[0737] In one embodiment, R.sup.Q21 is independently selected
from:
[0738] --CH.sub.2-- and, --CH.sub.2CH.sub.2--.
[0739] In one embodiment, R.sup.Q21 is independently
--CH.sub.2--.
[0740] In one embodiment, R.sup.Q21 is independently
--CH.sub.2CH.sub.2--.
[0741] In one embodiment, R.sup.Q21 is independently
--CH.sub.2--CH.dbd.CH--.
[0742] In one embodiment, R.sup.Q21 is independently cis
--CH.sub.2--CH.dbd.CH--.
[0743] In one embodiment, R.sup.Q21 is independently trans
--CH.sub.2--CH.dbd.CH--.
[0744] In one embodiment, R.sup.Q22 is independently selected
from:
[0745] --CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, --(CH.sub.2).sub.5--,
--(CH.sub.2).sub.6--;
[0746] --CH.dbd.CH--;
[0747] --CH.sub.2--CH.dbd.CH--;
[0748] --CH.dbd.CH--CH.dbd.CH--; and,
[0749] --CH.sub.2--CH.dbd.CH--CH.dbd.CH--.
[0750] In one embodiment, R.sup.Q22 is independently selected
from:
[0751] --CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.dbd.CH--, and
--CH.sub.2--CH.dbd.CH--.
[0752] In one embodiment, R.sup.Q22 is independently selected
from:
[0753] --CH.sub.2--, --CH.sub.2CH.sub.2--, and --CH.dbd.CH--.
[0754] The Acid Leader Group, Q.sup.2: Certain Phenylene-Containing
Embodiments
[0755] In one embodiment, Q.sup.2 is independently:
[0756] phenylene;
[0757] and is optionally substituted;
[0758] and has a backbone length of at least 4 atoms.
[0759] In one embodiment, Q.sup.2 is independently:
[0760] methylene-phenylene;
[0761] ethylene-phenylene;
[0762] and is optionally substituted;
[0763] and has a backbone length of at least 4 atoms.
[0764] In one embodiment, Q.sup.2 is independently:
[0765] phenylene-methylene;
[0766] phenylene-ethylene; or,
[0767] phenylene-ethenylene (also known as phenylene-vinylene);
[0768] and is optionally substituted;
[0769] and has a backbone length of at least 4 atoms.
[0770] In one embodiment, Q.sup.2 is independently:
[0771] methylene-phenylene-methylene;
[0772] methylene-phenylene-ethylene;
[0773] methylene-phenylene-ethenylene;
[0774] ethylene-phenylene-methylene;
[0775] ethylene-phenylene-ethylene;
[0776] ethylene-phenylene-ethenylene;
[0777] and is optionally substituted;
[0778] and has a backbone length of at least 4 atoms.
[0779] In the above phenylene, phenylene-alkylene,
alkylene-phenylene, and alkylene-phenylene-alkylene groups, the
phenylene linkage may be ortho (i.e., 1,2-), meta (i.e., 1,3-), or
para (i.e., 1,4-), and the phenylene group is optionally
substituted with from 1 to 4 substituents, R.sup.B: 42
[0780] In one embodiment, the phenylene linkage is meta or
para.
[0781] In one embodiment, the phenylene linkage is meta.
[0782] In one embodiment, the phenylene linkage is para.
[0783] In one embodiment, m is an integer from 0 to 4.
[0784] In one embodiment, m is an integer from 0 to 3.
[0785] In one embodiment, m is an integer from 0 to 2.
[0786] In one embodiment, m is 0 or 1.
[0787] In one embodiment, m is an integer from 1 to 4.
[0788] In one embodiment, m is an integer from 1 to 3.
[0789] In one embodiment, m is 1 or 2.
[0790] In one embodiment, m is 4.
[0791] In one embodiment, m is 3.
[0792] In one embodiment, m is 2.
[0793] In one embodiment, m is 1.
[0794] In one embodiment, m is 0.
[0795] In one embodiment, the phenylene group is unsubstituted.
[0796] In one embodiment, the phenylene group is optionally
substituted.
[0797] In one embodiment, the phenylene group is substituted.
[0798] Examples of substituents, R.sup.B, include, but are not
limited to, those described under the heading "Substituents"
below.
[0799] In one embodiment, the substituents, R.sup.B, are as defined
under the heading "The Cyclyl Group, Cy: Optionally Substituted
Phenyl: Substituents."
[0800] Examples of preferred substituents, R.sup.B, include, but
are not limited to, the following: fluoro, chloro, methyl, ethyl,
isopropyl, t-butyl, trifluoromethyl, hydroxy, methoxy, ethoxy,
isopropoxy, methylthio, amino, dimethylamino, diethylamino,
morpholino, acetamido, nitro, and phenyl.
[0801] In one embodiment, the compounds have the following formula,
in which Q.sup.2 is para-arylene: 43
[0802] In one embodiment, the compounds have the following formula,
in which Q.sup.2 is alkylene-meta/para-arylene: 44
[0803] In one embodiment, the compounds have the following formula,
in which Q.sup.2 is arylene-meta/para-alkylene: 45
[0804] In one embodiment, the compounds have the following formula,
in which Q.sup.2 is alkylene-arylene-meta/para-alkylene: 46
[0805] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "para-phenylene"): 47
[0806] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "methylene-meta/para-phenylene"): 48
[0807] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "methylene-meta-phenylene"): 49
[0808] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "unsubstituted methylene-meta-phenylene"):
50
[0809] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "ethylene-meta/para-phenylene"): 51
[0810] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "ethylene-meta-phenylene"): 52
[0811] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "unsubstituted ethylene-meta-phenylene"):
53
[0812] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "phenylene-meta/para-methylene"): 54
[0813] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "phenylene-meta-methylene"): 55
[0814] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "unsubstituted phenylene-meta-methylene"):
56
[0815] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "methylene-phenylene-meta/para-methylene"):
57
[0816] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "methylene-phenylene-meta-methylene"):
58
[0817] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "unsubstituted
methylene-phenylene-meta-methylene"): 59
[0818] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "ethylene-phenylene-meta/para-methylene"):
60
[0819] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "ethylene-phenylene-meta-methylene"): 61
[0820] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "unsubstituted
ethylene-phenylene-meta-methylene"): 62
[0821] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "phenylene-meta/para-trans-ethenylene"):
63
[0822] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "unsubstituted
phenylene-meta/para-trans-ethenylene"): 64
[0823] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "phenylene-meta-trans-ethenylene"): 65
[0824] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "unsubstituted
phenylene-meta-trans-ethenylene"): 66
[0825] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "phenylene-meta/para-ethylene"): 67
[0826] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "phenylene-meta-ethylene"): 68
[0827] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "unsubstituted phenylene-meta-ethylene"):
69
[0828] In one embodiment, Q.sup.2 has the following formula
(referred to herein as
"methylene-phenylene-meta/para-trans-ethenylene"): 70
[0829] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "unsubstituted
methylene-phenylene-meta/para-trans-ethenylene")- : 71
[0830] In one embodiment, Q.sup.2 has the following formula
(referred to herein as
"methylene-phenylene-meta-trans-ethenylene"): 72
[0831] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "unsubstituted
methylene-phenylene-meta-trans-ethenylene"): 73
[0832] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "methylene-phenylene-meta/para-ethylene"):
74
[0833] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "methylene-phenylene-meta-ethylene"): 75
[0834] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "unsubstituted
methylene-phenylene-meta-ethylene"): 76
[0835] In one embodiment, Q.sup.2 has the following formula
(referred to herein as
"ethylene-phenylene-meta/para-trans-ethenylene"): 77
[0836] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "ethylene-phenylene-meta-trans-ethenylene"):
78
[0837] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "unsubsfituted
ethylene-phenylene-meta-trans-ethenylene"): 79
[0838] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "ethylene-phenylene-meta/para-ethylene"):
80
[0839] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "ethylene-phenylene-meta-ethylene"): 81
[0840] In one embodiment, Q.sup.2 has the following formula
(referred to herein as "unsubstituted
ethylene-phenylene-meta-ethylene"): 82
[0841] In one embodiment, Q.sup.2 additionally has a backbone
length as described above under the heading "The Acid Leader Group,
Q.sup.2: Backbone Length."
EXAMPLES OF SPECIFIC EMBODIMENTS
[0842] Some individual embodiments of the present invention include
the following compounds.
1 1. 83 PX117402 (Ex 140) 2. 84 PX117403 (Ex 141) 3. 85 PX117404
(Ex 142) 4. 86 PX117764 (Ex 143) 5. 87 PX117768 (Ex 144) 6. 88
PX118490 (Ex 40) 7. 89 PX118491 (Ex 41) 8. 90 PX118791 (Ex 145) 9.
91 PX118792 (Ex 146) 10. 92 PX118793 (Ex 147) 11. 93 PX118794 (Ex
148) 12. 94 PX118807 (Ex 45) 13. 95 PX118810 (Ex 42) 14. 96
PX118811 (Ex 43) 15. 97 PX118812 (Ex 44) 16. 98 PX118830 (Ex 149)
17. 99 PX118831 (Ex 150) 18. 100 PX118832 (Ex 151) 19. 101 PX118844
(Ex 163) 20. 102 PX118845 (Ex 164) 21. 103 PX118846 (Ex 152) 22.
104 PX118847 (Ex 153) 23. 105 PX118848 (Ex 165) 24. 106 PX118849
(Ex 154) 25. 107 PX118850 (Ex 166) 26. 108 PX118859 (Ex 174) 27.
109 PX118860 (Ex 175) 28. 110 PX118870 (Ex 52) 29. 111 PX118871 (Ex
53) 30. 112 PX118872 (Ex 54) 31. 113 PX118873 (Ex 55) 32. 114
PX118874 (Ex 56) 33. 115 PX118875 (Ex 57) 34. 116 PX118876 (Ex 58)
35. 117 PX118877 (Ex 59) 36. 118 PX118878 (Ex 60) 37. 119 PX118882
(Ex 72) 38. 120 PX118891 (Ex 74) 39. 121 PX118892 (Ex 75) 40. 122
PX118893 (Ex 61) 41. 123 PX118894 (Ex 62) 42. 124 PX118898 (Ex 176)
43. 125 PX118899 (Ex 177) 44. 126 PX118900 (Ex 178) 45. 127
PX118901 (Ex 179) 46. 128 PX118902 (Ex 180) 47. 129 PX118903 (Ex
181) 48. 130 PX118904 (Ex 182) 49. 131 PX118905 (Ex 76) 50. 132
PX118906 (Ex 77) 51. 133 PX118907 (Ex 78) 52. 134 PX118908 (Ex 183)
53. 135 PX118909 (Ex 184) 54. 136 PX118910 (Ex 79) 55. 137 PX118911
(Ex 80) 56. 138 PX118913 (Ex 63) 57. 139 PX118914 (Ex 64) 58. 140
PX118918 (Ex 73) 59. 141 PX118927 (Ex 155) 60. 142 PX118928 (Ex
167) 61. 143 PX118929 (Ex 168) 62. 144 PX118930 (Ex 156) 63. 145
PX118931 (Ex 157) 64. 146 PX118932 (Ex 158) 65. 147 PX118933 (Ex
46) 66. 148 PX118934 (Ex 48) 67. 149 PX118935 (Ex 49) 68. 150
PX118937 (Ex 70) 69. 151 PX118951 (Ex 47) 70. 152 PX118965 (Ex 71)
71. 153 PX118967 (Ex 159) 72. 154 PX118968 (Ex 169) 73. 155
PX118969 (Ex 170) 74. 156 PX118970 (Ex 171) 75. 157 PX118971 (Ex
50) 76. 158 PX118972 (Ex 51) 77. 159 PX118978 (Ex 172) 78. 160
PX118989 (Ex 160) 79. 161 PX118990 (Ex 161) 80. 162 PX118991 (Ex
162) 81. 163 PX118994 (Ex 173) 82. 164 83. 165 84. 166 85. 167 86.
168 87. 169 88. 170 89. 171 90. 172 91. 173 92. 174 93. 175 94. 176
95. 177 96. 178 97. 179 98. 180 99. 181 100. 182
[0843] Note that, where the above examples are salts (e.g.,
PX118932, PX118882), other analogous salts may also be
prepared.
[0844] Chemical Terms
[0845] The term "carbo," "carbyl," "hydrocarbo" and "hydrocarbyl,"
as used herein, pertain to compounds and/or groups which have only
carbon and hydrogen atoms (but see "carbocyclic" below).
[0846] The term "hetero," as used herein, pertains to compounds
and/or groups which have at least one heteroatom, for example,
multivalent heteroatoms (which are also suitable as ring
heteroatoms) such as boron, silicon, nitrogen, phosphorus, oxygen,
sulfur, and selenium (more commonly nitrogen, oxygen, and sulfur)
and monovalent heteroatoms, such as fluorine, chlorine, bromine,
and iodine.
[0847] The term "saturated," as used herein, pertains to compounds
and/or groups which do not have any carbon-carbon double bonds or
carbon-carbon triple bonds.
[0848] The term "unsaturated," as used herein, pertains to
compounds and/or groups which have at least one carbon-carbon
double bond or carbon-carbon triple bond.
[0849] The term "aliphatic," as used herein, pertains to compounds
and/or groups which are linear or branched, but not cyclic (also
known as "acyclic" or "open-chain" groups).
[0850] The term "ring," as used herein, pertains to a closed ring
of from 3 to 10 covalently linked atoms, more preferably 3 to 8
covalently linked atoms, yet more preferably 5 to 6 covalently
linked atoms. A ring may be an alicyclic ring or an aromatic ring.
The term "alicyclic ring," as used herein, pertains to a ring which
is not an aromatic ring.
[0851] The term "carbocyclic ring," as used herein, pertains to a
ring wherein all of the ring atoms are carbon atoms.
[0852] The term "carboaromatic ring," as used herein, pertains to
an aromatic ring wherein all of the ring atoms are carbon
atoms.
[0853] The term "heterocyclic ring," as used herein, pertains to a
ring wherein at least one of the ring atoms is a multivalent ring
heteroatom, for example, nitrogen, phosphorus, silicon, oxygen, or
sulfur, though more commonly nitrogen, oxygen, or sulfur.
Preferably, the heterocyclic ring has from 1 to 4 heteroatoms.
[0854] The term "cyclic compound," as used herein, pertains to a
compound which has at least one ring. The term "cyclyl," as used
herein, pertains to a monovalent moiety obtained by removing a
hydrogen atom from a ring atom of a cyclic compound.
[0855] Where a cyclic compound has two or more rings, they may be
fused (e.g., as in naphthalene), bridged (e.g., as in norbornane),
spiro (e.g., as in spiro[3.3]heptane), or a combination thereof.
Cyclic compounds with one ring may be referred to as "monocyclic"
or "mononuclear," whereas cyclic compounds with two or more rings
may be referred to as "polycyclic" or "polynuclear."
[0856] The term "carbocyclic compound," as used herein, pertains to
a cyclic compound which has only carbocyclic ring(s).
[0857] The term "heterocyclic compound," as used herein, pertains
to a cyclic compound which has at least one heterocyclic ring.
[0858] The term "aromatic compound," as used herein, pertains to a
cyclic compound which has at least one aromatic ring.
[0859] The term "carboaromatic compound," as used herein, pertains
to a cyclic compound which has only carboaromatic ring(s).
[0860] The term "heteroaromatic compound," as used herein, pertains
to a cyclic compound which has at least one heteroaromatic
ring.
[0861] The term "monodentate substituents," as used herein,
pertains to substituents which have one point of covalent
attachment.
[0862] The term "monovalent monodentate substituents," as used
herein, pertains to substituents which have one point of covalent
attachment, via a single bond. Examples of such substituents
include halo, hydroxy, and alkyl.
[0863] The term "multivalent monodentate substituents," as used
herein, pertains to substituents which have one point of covalent
attachment, but through a double bond or triple bond. Examples of
such substituents include oxo, imino, alkylidene, and
alklidyne.
[0864] The term "bidentate substituents," as used herein, pertains
to substituents which have two points of covalent attachment, and
which act as a linking group between two other moieties. Examples
of such substituents include alkylene and arylene.
[0865] Substituents
[0866] The phrase "optionally substituted," as used herein,
pertains to a parent group which may be unsubstituted or which may
be substituted.
[0867] Unless otherwise specified, the term "substituted," as used
herein, pertains to a parent group which bears one or more
substituents. The term "substituent" is used herein in the
conventional sense and refers to a chemical moiety which is
covalently attached to, appended to, or if appropriate, fused to, a
parent group. A wide variety of substituents are well known, and
methods for their formation and introduction into a variety of
parent groups are also well known.
[0868] The substituents are described in more detail below.
[0869] Alkyl: The term "alkyl," as used herein, pertains to a
monovalent moiety obtained by removing a hydrogen atom from a
carbon atom of a hydrocarbon compound having from 1 to 20 carbon
atoms (unless otherwise specified), which may be aliphatic or
alicyclic, and which may be saturated, partially unsaturated, or
fully unsaturated. Thus, the term "alkyl" Includes the sub-classes
alkenyl, alkynyl, cycloalkyl, etc., discussed below.
[0870] In this context, the prefixes (e.g., C.sub.1-4, C.sub.1-7,
C.sub.1-20, C.sub.2-7, C.sub.3-7, etc.) denote the number of carbon
atoms, or range of number of carbon atoms. For example, the term
"C.sub.1-4alkyl," as used herein, pertains to an alkyl group having
from 1 to 4 carbon atoms. Examples of groups of alkyl groups
include C.sub.1-4alkyl ("lower alkyl"), C.sub.1-7alkyl, and
C.sub.1-20alkyl.
[0871] Examples of (unsubstituted) saturated alkyl groups include,
but are not limited to, methyl (C.sub.1), ethyl (C.sub.2), propyl
(C.sub.3), butyl (C.sub.4), pentyl (C.sub.5), hexyl (C.sub.6),
heptyl (C.sub.7), octyl (C.sub.8), nonyl (C.sub.9), decyl
(C.sub.10), undecyl (C.sub.11), dodecyl (C.sub.12), tridecyl
(C.sub.13), tetradecyl (C.sub.14), pentadecyl (C.sub.15), and
eicodecyl (C.sub.20).
[0872] Examples of (unsubstituted) saturated linear alkyl groups
include, but are not limited to, methyl (C.sub.1), ethyl (C.sub.2),
n-propyl (C.sub.3), n-butyl (C.sub.4), n-pentyl (amyl) (C.sub.5),
n-hexyl (C.sub.6), and n-heptyl (C.sub.7).
[0873] Examples of (unsubstituted) saturated branched alkyl groups
include iso-propyl (C.sub.3), iso-butyl (C.sub.4), sec-butyl
(C.sub.4), tert-butyl (C.sub.4), iso-pentyl (C.sub.5), and
neo-pentyl (C.sub.5).
[0874] Cycloalkyl: The term "cycloalkyl," as used herein, pertains
to an alkyl group which is also a cyclyl group; that is, a
monovalent moiety obtained by removing a hydrogen atom from an
alicyclic ring atom of a cyclic hydrocarbon (carbocyclic) compound,
which moiety has from 3 to 20 ring atoms (unless otherwise
specified). Preferably, each ring has from 3 to 7 ring atoms.
[0875] Examples of (unsubstituted) saturated cylcoalkyl groups
include, but are not limited to, those derived from: cyclopropane
(C.sub.3), cyclobutane (C.sub.4), cyclopentane (C.sub.5),
cyclohexane (C.sub.6), cycloheptane (C.sub.7), norbornane
(C.sub.7), norpinane (C.sub.7), norcarane (C.sub.7), adamantane
(C.sub.10), and decalin (decahydronaphthalene) (C.sub.10).
[0876] Examples of (substituted) saturated cycloalkyl groups, which
are also referred to herein as "alkyl-cycloalkyl" groups, include,
but are not limited to, methylcyclopropyl, dimethylcyclopropyl,
methylcyclobutyl, dimethylcyclobutyl, methylcyclopentyl,
dimethylcyclopentyl, methylcyclohexyl, and dimethylcyclohexyl,
menthane, thujane, carane, pinane, bornane, norcarane, and
camphene.
[0877] Examples of (substituted) unsaturated cyclic alkenyl groups,
which are also referred to herein as "alkyl-cycloalkenyl" groups,
include, but are not limited to, methylcyclopropenyl,
dimethylcyclopropenyl, methylcyclobutenyl, dimethylcyclobutenyl,
methylcyclopentenyl, dimethylcyclopentenyl, methylcyclohexenyl, and
dimethylcyclohexenyl.
[0878] Examples of (substituted) cycloalkyl groups, with one or
more other rings fused to the parent cycloalkyl group, include, but
are not limited to, those derived from: indene (C.sub.9), indan
(e.g., 2,3-dihydro-1H-indene) (C.sub.9), tetraline
(1,2,3,4-tetrahydronaphthalen- e (C.sub.10), acenaphthene
(C.sub.12), fluorene (C.sub.13), phenalene (C.sub.13),
acephenanthrene (C.sub.15), aceanthrene (C.sub.16). For example,
2H-inden-2-yl is a C.sub.5cycloalkyl group with a substituent
(phenyl) fused thereto.
[0879] Alkenyl: The term "alkenyl," as used herein, pertains to an
alkyl group having one or more carbon-carbon double bonds. Examples
of groups of alkenyl groups include C.sub.2-4alkenyl,
C.sub.2-7alkenyl, C.sub.2-20alkenyl.
[0880] Examples of (unsubstituted) unsaturated alkenyl groups
include, but are not limited to, ethenyl (vinyl,
--CH.dbd.CH.sub.2), 1-propenyl (--CH.dbd.CH--CH.sub.3), 2-propenyl
(allyl, --CH--CH.dbd.CH.sub.2), isopropenyl
(--C(CH.sub.3).dbd.CH.sub.2), butenyl (C.sub.4), pentenyl
(C.sub.5), and hexenyl (C.sub.6).
[0881] Examples of (unsubstituted) unsaturated cyclic alkenyl
groups, which are also referred to herein as "cycloalkenyl" groups,
include, but are not limited to, cyclopropenyl (C.sub.3),
cyclobutenyl (C.sub.4), cyclopentenyl (C.sub.5), and cyclohexenyl
(C.sub.6).
[0882] Alkynyl: The term "alkynyl," as used herein, pertains to an
alkyl group having one or more carbon-carbon triple bonds. Examples
of groups of alkynyl groups include C.sub.2-4alkynyl,
C.sub.2-7alkynyl, C.sub.2-20alkynyl.
[0883] Examples of (unsubstituted) unsaturated alkynyl groups
include, but are not limited to, ethynyl (ethinyl, --C.ident.CH)
and 2-propynyl (propargyl, --CH.sub.2--C.ident.CH).
[0884] Alkylidene: The term "alkylidene," as used herein, pertains
to a divalent monodentate moiety obtained by removing two hydrogen
atoms from a carbon atom of a hydrocarbon compound having from 1 to
20 carbon atoms (unless otherwise specified), which may be
aliphatic or alicyclic, or a combination thereof, and which may be
saturated, partially unsaturated, or fully unsaturated. Examples of
groups of alkylidene groups include C.sub.1-4alkylidene,
C.sub.1-7alkylidene, C.sub.1-20alkylidene.
[0885] Examples of alkylidene groups include, but are not limited
to, methylidene (.dbd.CH.sub.2), ethylidene (.dbd.CH--CH.sub.3),
vinylidene (.dbd.C.dbd.CH.sub.2), and isopropylidene
(.dbd.C(CH.sub.3).sub.2). An example of a substituted alkylidene is
benzylidene (.dbd.CH-Ph).
[0886] Alkylidyne: The term "alkylidyne," as used herein, pertains
to a trivalent monodentate moiety obtained by removing three
hydrogen atoms from a carbon atom of a hydrocarbon compound having
from 1 to 20 carbon atoms (unless otherwise specified), which may
be aliphatic or alicyclic, or a combination thereof, and which may
be saturated, partially unsaturated, or fully unsaturated. Examples
of groups of alkylidyne groups include C.sub.1-4alkylidyne,
C.sub.1-7alkylidyne, C.sub.1-20alkylidyne.
[0887] Examples of alkylidyne groups include, but are not limited
to, methylidyne (.ident.CH) and ethylidyne
(.ident.C--CH.sub.3).
[0888] Carbocyclyl: The term "carbocyclyl," as used herein,
pertains to a monovalent moiety obtained by removing a hydrogen
atom from a ring atom of a carbocyclic compound, which moiety has
from 3 to 20 ring atoms (unless otherwise specified). Preferably,
each ring has from 3 to 7 ring atoms.
[0889] In this context, the prefixes (e.g., C.sub.3-20, C.sub.3-7,
C.sub.5-6, etc.) denote the number of ring atoms, or range of
number of ring atoms. For example, the term "C.sub.5-6carbocyclyl,"
as used herein, pertains to a carbocyclyl group having 5 or 6 ring
atoms. Examples of groups of carbocyclyl groups include
C.sub.3-20carbocyclyl, C.sub.3-10carbocyclyl,
C.sub.5-10carbocyclyl, C.sub.3-7carbocyclyl, and
C.sub.5-7carbocyclyl.
[0890] Examples of carbocyclic groups include, but are not limited
to, those described above as cycloalkyl groups; and those described
below as carboaryl groups.
[0891] Heterocyclyl: The term "heterocyclyl," as used herein,
pertains to a monovalent moiety obtained by removing a hydrogen
atom from a ring atom of a heterocyclic compound, which moiety has
from 3 to 20 ring atoms (unless otherwise specified), of which from
1 to 10 are ring heteroatoms. Preferably, each ring has from 3 to 7
ring atoms, of which from 1 to 4 are ring heteroatoms.
[0892] In this context, the prefixes (e.g., C.sub.3-20, C.sub.3-7,
C.sub.5-6, etc.) denote the number of ring atoms, or range of
number of ring atoms, whether carbon atoms or heteroatoms. For
example, the term "C.sub.5-6heterocyclyl," as used herein, pertains
to a heterocyclyl group having 5 or 6 ring atoms. Examples of
groups of heterocyclyl groups include C.sub.3-20heterocyclyl,
C.sub.3-7heterocyclyl, C.sub.5-7heterocyclyl, and
C.sub.5-6heterocyclyl.
[0893] Examples of (non-aromatic) monocyclic heterocyclyl groups
include, but are not limited to, those derived from:
[0894] N.sub.1: aziridine (C.sub.3), azetidine (C.sub.4),
pyrrolidine (tetrahydropyrrole) (C.sub.5), pyrroline (e.g.,
3-pyrroline, 2,5-dihydropyrrole) (C.sub.5), 2H-pyrrole or
3H-pyrrole (isopyrrole, isoazole) (C.sub.5), piperidine (C.sub.6),
dihydropyridine (C.sub.6), tetrahydropyridine (C.sub.6), azepine
(C.sub.7);
[0895] O.sub.1: oxirane (C.sub.3), oxetane (C.sub.4), oxolane
(tetrahydrofuran) (C.sub.5), oxole (dihydrofuran) (C.sub.5), oxane
(tetrahydropyran) (C.sub.6), dihydropyran (C.sub.6), pyran
(C.sub.6), oxepin (C.sub.7);
[0896] S.sub.1: thiirane (C.sub.3), thietane (C.sub.4), thiolane
(tetrahydrothiophene) (C.sub.5), thiane (tetrahydrothiopyran)
(C.sub.6), thiepane (C.sub.7);
[0897] O.sub.2: dioxolane (C.sub.5), dioxane (C.sub.6), and
dioxepane (C.sub.7);
[0898] O.sub.3: trioxane (C.sub.6);
[0899] N.sub.2: imidazolidine (C.sub.5), pyrazolidine (diazolidine)
(C.sub.5), imidazoline (C.sub.5), pyrazoline (dihydropyrazole)
(C.sub.5), piperazine (C.sub.6);
[0900] N.sub.1O.sub.1: tetrahydrooxazole (C.sub.5), dihydrooxazole
(C.sub.5), tetrahydroisoxazole (C.sub.5), dihydroisoxazole
(C.sub.5), morpholine (C.sub.6), tetrahydrooxazine (C.sub.6),
dihydrooxazine (C.sub.6), oxazine (C.sub.6);
[0901] N.sub.1S.sub.1: thiazoline (C.sub.5), thiazolidine
(C.sub.5), thiomorpholine (C.sub.6);
[0902] N.sub.2O.sub.1: oxadiazine (C.sub.6);
[0903] O.sub.1S.sub.1: oxathiole (C.sub.5) and oxathiane (thioxane)
(C.sub.6); and,
[0904] N.sub.1O.sub.1S.sub.1: oxathiazine (C.sub.6).
[0905] Examples of substituted (non-aromatic) monocyclic
heterocyclyl groups include saccharides, in cyclic form, for
example, furanoses (C.sub.5), such as arabinofuranose,
lyxofuranose, ribofuranose, and xylofuranse, and pyranoses
(C.sub.6), such as allopyranose, altropyranose, glucopyranose,
mannopyranose, gulopyranose, idopyranose, galactopyranose, and
talopyranose.
[0906] Examples of heterocyclyl groups which are also heteroaryl
groups are described below with aryl groups.
[0907] Aryl: The term "aryl," as used herein, pertains to a
monovalent moiety obtained by removing a hydrogen atom from an
aromatic ring atom of an aromatic compound, which moiety has from 3
to 20 ring atoms (unless otherwise specified). Preferably, each
ring has from 5 to 7 ring atoms.
[0908] In this context, the prefixes (e.g., C.sub.3-20, C.sub.5-7,
C.sub.5-6, etc.) denote the number of ring atoms, or range of
number of ring atoms, whether carbon atoms or heteroatoms. For
example, the term "C.sub.5-6aryl," as used herein, pertains to an
aryl group having 5 or 6 ring atoms. Examples of groups of aryl
groups include C.sub.3-20aryl, C.sub.3-12aryl, C.sub.5-12aryl,
C.sub.5-7aryl, and C.sub.5-6aryl.
[0909] The ring atoms may be all carbon atoms, as in "carboaryl
groups" (e.g., C.sub.5-20carboaryl).
[0910] Examples of carboaryl groups include, but are not limited
to, those derived from benzene (i.e., phenyl) (C.sub.6),
naphthalene (C.sub.10), azulene (C.sub.10), anthracene (C.sub.14),
phenanthrene (C.sub.14), naphthacene (C.sub.18), and pyrene
(C.sub.16).
[0911] Examples of aryl groups which comprise fused rings, at least
one of which is an aromatic ring, include, but are not limited to,
groups derived from indene (C.sub.9), isoindene (C.sub.9), and
fluorene (C.sub.13).
[0912] Alternatively, the ring atoms may include one or more
heteroatoms, as in "heteroaryl groups" (e.g.,
C.sub.5-20heteroaryl).
[0913] Examples of monocyclic heteroaryl groups include, but are
not limited to, those derived from:
[0914] N.sub.1: pyrrole (azole) (C.sub.5), pyridine (azine)
(C.sub.6);
[0915] O.sub.1: furan (oxole) (C.sub.5);
[0916] S.sub.1: thiophene (thiole) (C.sub.5);
[0917] N.sub.1O.sub.1: oxazole (C.sub.5), isoxazole (C.sub.5),
isoxazine (C.sub.6);
[0918] N.sub.2O.sub.1: oxadiazole (furazan) (C.sub.5);
[0919] N.sub.3O.sub.1: oxatriazole (C.sub.5);
[0920] N.sub.1S.sub.1: thiazole (C.sub.5), isothiazole
(C.sub.5);
[0921] N.sub.2: imidazole (1,3-diazole) (C.sub.5), pyrazole
(1,2-diazole) (C.sub.5), pyridazine (1,2-diazine) (C.sub.6),
pyrimidine (1,3-diazine) (C.sub.6) (e.g., cytosine, thymine,
uracil), pyrazine (1,4-diazine) (C.sub.6);
[0922] N.sub.3: triazole (C.sub.5), triazine (C.sub.6); and,
[0923] N.sub.4: tetrazole (C.sub.5).
[0924] Examples of heterocyclic groups (some of which are also
heteroaryl groups) which comprise fused rings, include, but are not
limited to:
[0925] C.sub.9heterocyclic groups (with 2 fused rings) derived from
benzofuran (O.sub.1), isobenzofuran (O.sub.1), indole (N.sub.1),
isoindole (N.sub.1), indolizine (N.sub.1), indoline (N.sub.1),
isoindoline (N.sub.1), purine (N.sub.4) (e.g., adenine, guanine),
benzimidazole (N.sub.2), indazole (N.sub.2), benzoxazole
(N.sub.1O.sub.1), benzisoxazole (N.sub.1O.sub.1), benzodioxole
(O.sub.2), benzofurazan (N.sub.2O.sub.1), benzotriazole (N.sub.3),
benzothiofuran (S.sub.1), benzothiazole (N.sub.1S.sub.1),
benzothiadiazole (N.sub.2S);
[0926] C.sub.10heterocyclic groups (with 2 fused rings) derived
from chromene (O.sub.1), isochromene (O.sub.1), chroman (O.sub.1),
isochroman (O.sub.1), benzodioxan (O.sub.2), quinoline (N.sub.1),
isoquinoline (N.sub.1), quinolizine (N.sub.1), benzoxazine
(N.sub.1O.sub.1), benzodiazine (N.sub.2), pyridopyridine (N.sub.2),
quinoxaline (N.sub.2), quinazoline (N.sub.2), cinnoline (N.sub.2),
phthalazine (N.sub.2), naphthyridine (N.sub.2), pteridine
(N.sub.4);
[0927] C.sub.13heterocyclic groups (with 3 fused rings) derived
from carbazole (N.sub.1), dibenzofuran (O.sub.1), dibenzothiophene
(S.sub.1), carboline (N.sub.2), perimidine (N.sub.2), pyridoindole
(N.sub.2); and,
[0928] C.sub.14heterocyclic groups (with 3 fused rings) derived
from acridine (N.sub.1), xanthene (O.sub.1), thioxanthene
(S.sub.1), oxanthrene (O.sub.2), phenoxathiin (O.sub.1S.sub.1),
phenazine (N.sub.2), phenoxazine (N.sub.1O.sub.1), phenothiazine
(N.sub.1S.sub.1), thianthrene (S.sub.2), phenanthridine (N.sub.1),
phenanthroline (N.sub.2), phenazine (N.sub.2).
[0929] Heterocyclic groups (including heteroaryl groups) which have
a nitrogen ring atom in the form of an --NH-- group may be
N-substituted, that is, as --NR--. For example, pyrrole may be
N-methyl substituted, to give N-methypyrrole. Examples of
N-substituents include, but are not limited to C.sub.1-7alkyl,
C.sub.3-20heterocyclyl, C.sub.5-20aryl, and acyl groups.
[0930] Heterocyclic groups (including heteroaryl groups) which have
a nitrogen ring atom in the form of an --N.dbd. group may be
substituted in the form of an N-oxide, that is, as
--N(.fwdarw.O).dbd. (also denoted --N.sup.+(.fwdarw.O.sup.-).dbd.).
For example, quinoline may be substituted to give quinoline
N-oxide; pyridine to give pyridine N-oxide; benzofurazan to give
benzofurazan N-oxide (also known as benzofuroxan).
[0931] Cyclic groups may additionally bear one or moe oxo (.dbd.O)
groups on ring carbon atoms. Monocyclic examples of such groups
include, but are not limited to, those derived from:
[0932] C.sub.5: cyclopentanone, cyclopentenone,
cyclopentadienone;
[0933] C.sub.6: cyclohexanone, cyclohexenone, cyclohexadienone;
[0934] O.sub.1: furanone (C.sub.5), pyrone (C.sub.6);
[0935] N.sub.1: pyrrolidone (pyrrolidinone) (C.sub.5), piperidinone
(piperidone) (C.sub.6), piperidinedione (C.sub.6);
[0936] N.sub.2: imidazolidone (imidazolidinone) (C.sub.5),
pyrazolone (pyrazolinone) (C.sub.5), piperazinone
[0937] (C.sub.6), piperazinedione (C.sub.6), pyridazinone
(C.sub.6), pyrimidinone (C.sub.6) (e.g., cytosine), pyrimidinedione
(C.sub.6) (e.g., thymine, uradl), barbituric acid (Ca);
[0938] N.sub.1S.sub.1: thiazolone (C.sub.5), isothiazolone
(C.sub.5);
[0939] N.sub.1O.sub.1: oxazolinone (C.sub.5).
[0940] Polycyclic examples of such groups include, but are not
limited to, those derived from:
[0941] C.sub.9: indenedione;
[0942] C.sub.10: tetralone, decalone;
[0943] C.sub.14: anthrone, phenanthrone;
[0944] N.sub.1: oxindole (C.sub.9);
[0945] O.sub.1: benzopyrone (e.g., coumarin, isocoumarin, chromone)
(C.sub.10);
[0946] N.sub.1O.sub.1: benzoxazolinone (C.sub.9), benzoxazolinone
(C.sub.10);
[0947] N.sub.2: quinazolinedione (C.sub.10);
[0948] N.sub.4: purinone (C.sub.9) (e.g., guanine).
[0949] Still more examples of cyclic groups which bear one or more
oxo (.dbd.O) groups on ring carbon atoms include, but are not
limited to, those derived from:
[0950] cyclic anhydrides (--C(.dbd.O)--O--C(.dbd.O)-- in a ring),
including but not limited to maleic anhydride (C.sub.5), succinic
anhydride (C.sub.5), and glutaric anhydride (C.sub.6);
[0951] cyclic carbonates (--O--C(--O)--O-- in a ring), such as
ethylene carbonate (C.sub.5) and 1,2-propylene carbonate
(C.sub.5);
[0952] imides (--C(.dbd.O)--NR--C(.dbd.O)-- in a ring), including
but not limited to, succinimide (C.sub.5), maleimide (C.sub.5),
phthalimide, and glutarimide (C.sub.6);
[0953] lactones (cyclic esters, O--C(.dbd.O)-- in a ring),
including, but not limited to, .beta.-propiolactone,
.gamma.-butyrolactone, .delta.-valerolactone (2-piperidone), and
.epsilon.-caprolactone;
[0954] lactams (cyclic amides, --NR--C(.dbd.O)-- in a ring),
including, but not limited to, .beta.-propiolactam (C.sub.4),
.gamma.-butyrolactam (2-pyrrolidone) (C.sub.5),
.delta.-valerolactam (C.sub.6), and .epsilon.-caprolactam
(C.sub.7);
[0955] cyclic carbamates (--O--C(.dbd.O)--NR-- in a ring), such as
2-oxazolidone (C.sub.5);
[0956] cyclic ureas (--NR--C(.dbd.O)--NR-- in a ring), such as
2-imidazolidone (C.sub.5) and pyrimidine-2,4-dione (e.g., thymine,
uracil) (C.sub.6).
[0957] The above alkyl, alkylidene, alkylidyne, heterocyclyl, and
aryl groups, whether alone or part of another substituent, may
themselves optionally be substituted with one or more groups
selected from themselves and the additional substituents listed
below.
[0958] Hydrogen: --H. Note that if the substituent at a particular
position is hydrogen, it may be convenient to refer to the compound
as being "unsubstituted" at that position.
[0959] Halo: --F, --Cl, --Br, and --I.
[0960] Hydroxy: --OH.
[0961] Ether: --OR, wherein R is an ether substituent, for example,
a C.sub.1-7alkyl group (also referred to as a C.sub.1-7alkoxy
group, discussed below), a C.sub.3-20heterocyclyl group (also
referred to as a C.sub.3-20heterocyclyloxy group), or a
C.sub.5-20aryl group (also referred to as a C.sub.5-20aryloxy
group), preferably a C.sub.1-7alkyl group.
[0962] C.sub.1-7alkoxy: --OR, wherein R is a C.sub.1-7alkyl group.
Examples of C.sub.1-7alkoxy groups include, but are not limited to,
--OMe (methoxy), --OEt (ethoxy), --O(nPr) (n-propoxy), --O(iPr)
(isopropoxy), --O(nBu) (n-butoxy), --O(sBu) (sec-butoxy), --O(iBu)
(isobutoxy), and --O(tBu) (tert-butoxy).
[0963] Acetal: --CH(OR.sup.1)(OR.sup.2), wherein R.sup.1 and
R.sup.2 are independently acetal substituents, for example, a
C.sub.1-7alkyl group, a C.sub.3-20heterocyclyl group, or a
C.sub.5-20aryl group, preferably a C.sub.1-7alkyl group, or, in the
case of a "cyclic" acetal group, R.sup.1 and R.sup.2, taken
together with the two oxygen atoms to which they are attached, and
the carbon atoms to which they are attached, form a heterocyclic
ring having from 4 to 8 ring atoms. Examples of acetal groups
include, but are not limited to, --CH(OMe).sub.2, --CH(OEt).sub.2,
and --CH(OMe)(OEt).
[0964] Hemiacetal: --CH(OH)(OR.sup.1), wherein R.sup.1 is a
hemiacetal substituent, for example, a C.sub.1-7alkyl group, a
C.sub.3-20heterocyclyl group, or a C.sub.5-20aryl group, preferably
a C.sub.1-7alkyl group. Examples of hemiacetal groups include, but
are not limited to, --CH(OH)(OMe) and --CH(OH)(OEt).
[0965] Ketal: --CR(OR.sup.1)(OR.sup.2), where R.sup.1 and R.sup.2,
are as defined for acetals, and R is a ketal substituent other than
hydrogen, for example, a C.sub.1-7alkyl group, a
C.sub.3-20heterocyclyl group, or a C.sub.5-20aryl group, preferably
a C.sub.1-7alkyl group. Examples ketal groups include, but are not
limited to, --C(Me)(OMe).sub.2, --C(Me)(OEt).sub.2,
--C(Me)(OMe)(OEt), --C(Et)(OMe).sub.2, --C(Et)(OEt).sub.2, and
--C(Et)(OMe)(OEt).
[0966] Hemiketal: --CR(OH)(OR.sup.1), where R.sup.1 is as defined
for hemiacetals, and R is a hemiketal substituent other than
hydrogen, for example, a C.sub.1-7alkyl group, a
C.sub.3-20heterocyclyl group, or a C.sub.5-20aryl group, preferably
a C.sub.1-7alkyl group. Examples of hemiacetal groups include, but
are not limited to, --C(Me)(OH)(OMe), --C(Et)(OH)(OMe),
--C(Me)(OH)(OEt), and --C(Et)(OH)(OEt).
[0967] Oxo (keto, -one): .dbd.O.
[0968] Thione (thioketone): .dbd.S.
[0969] Imino (imine): .dbd.NR, wherein R is an imino substituent,
for example, hydrogen, C.sub.1-7alkyl group, a
C.sub.3-20hetercyclyl group, or a C.sub.5-20aryl group, preferably
hydrogen or a C.sub.1-7alkyl group. Examples of ester groups
include, but are not limited to, .dbd.NH, .dbd.NMe, .dbd.NEt, and
.dbd.NPh.
[0970] Formyl (carbaldehyde, carboxaldehyde): --C(.dbd.O)H.
[0971] Acyl (keto): --C(.dbd.O)R, wherein R is an acyl substituent,
for example, a C.sub.1-7alkyl group (also referred to as
C.sub.1-7alkylacyl or C.sub.1-7alkanoyl), a C.sub.3-20heterocyclyl
group (also referred to as C.sub.3-20heterocyclylacyl), or a
C.sub.5-20aryl group (also referred to as C.sub.5-20arylacyl),
preferably a C.sub.1-7alkyl group. Examples of acyl groups include,
but are not limited to, --C(.dbd.O)CH.sub.3 (acetyl),
--C(.dbd.O)CH.sub.2CH.sub.3 (propionyl),
--C(.dbd.O)C(CH.sub.3).sub.3 (t-butyryl), and --C(.dbd.O)Ph
(benzoyl, phenone). mm; mobile phase acetonitrile-0.1 M phosphate
buffer (pH 2.5), 50:50; sample concentration 1.0 mg/ml; flow rate
1.5 mL/min; detector UV 220 nm.) Anal. Calcd. for
C.sub.20H.sub.20F.sub.3N.sub.3O.sub.4S*0.1EtOAc- , %: C 52.78; H,
4.52; N, 9.05. Found, %: C 52.74, H 4.36, N 8.88.
EXAMPLE 61
(E)-N-Hydroxy-3-(3-{[4-(3-nitrophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-pr-
openamide (PX118893)
[0972] The title compound was obtained using methods analogous to
those described above. M.p. 162.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO) .delta.: 2.94-3.20 (4H, m); 3.45-3.69 (4H,
m); 6.65 (1H, d, J=16.0 Hz); 7.02 (2H, d, J=9.0 Hz); 7.58 (1H, d,
J=16.0 Hz); 7.62-7.83 (2H, m); 7.84-8.20 (4H, m); 10.20 (2H, br s).
HPLC analysis on Omnisphere 5 C.sub.18: impurities 2.0% (column
size 4.6.times.150 mm; mobile phase acetonitrile-0.1 M phosphate
buffer (pH 2.5), 40:60; sample concentration 0.3 mg/ml; flow rate
1.5 mL/min; detector UV 220 nm). Anal. Calcd. for
C.sub.19H.sub.20N.sub.4O.sub.6S containing 2.3% inorganic material,
%: C 51.56, H 4.55, N 12.66. Found, %: C, 51.54; H, 4.50; N,
12.57.
EXAMPLE 62
(E)-N-Hydroxy-3-(3-{[4-(2-pyrimidinyl)-1-piperazinyl]sulfonyl}-phenyl)-2-p-
ropenamide (PX118894)
[0973] The title compound was obtained using methods analogous to
those described above. M.p. 200.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO), .delta.: 2.78-3.15 (4H, m); 3.63-3.94 (4H,
m); 6.58 (1H, d, J=16.0 Hz); 6.63 (1H, t, J=6.4 Hz); 7.56 (1H, d.
J=16.0 Hz); 7.57-8.12 (4H, m); 8.34 (2H, d, J=6.4 Hz); 9.16 (1H, br
s); 10.80 ppm (1H, br s). HPLC analysis on Alltima C.sub.18:
impurities 4.8% (column size: 4.6.times.150 mm; mobile phase
acetonitrile-0.1 M phosphate buffer (pH 2.5), 30:70; sample
concentration 1.0 mg/ml; flow rate 1.15 mL/min; detector UV 254
nm.) Anal. Calcd for C.sub.17H.sub.19N.sub.5O.sub.4S, %: C, 52.43;
H, 4.92; N, 17.98. Found, %: C 62.37, H 4.89, N 17.69.
EXAMPLE 63
(E)-3-(3-{[4-(2,2-Diphenylethyl)-I-piperazinyl]sulfonyl}phenyl)-N-hydroxy--
2-propenamide (PX118913)
[0974] The title compound was obtained using methods analogous to
those described above. M.p. 117.degree. C. (decomposes). .sup.1H
NMR (DMSO-d.sub.6, HMDSO), .delta.: 2.42-2.62 (4H, m, overlapped
with a signal of DMSO); 2.70-2.87 (4H, m); 2.92 (2H, d, J=7.3 Hz);
4.18 (1H t, J=7.3 Hz); 6.58 (1H, d, J=15.8 Hz); 7.02-7.35 (10H, m);
7.53 (1H, d, J=15.8 Hz); 7.61-7.70 (2H, m); 7.80-7.92 (2H, m); 9.14
(1H, br s); 10.80 ppm (1H, br s). HPLC analysis on Omnisphere
C.sub.18: impurities 4.5% (column size 4.6.times.150 mm; mobile
phase acetonitrile-0.1 M phosphate buffer (pH 2.5), 40:60; sample
concentration 0.5 mg/ml; flow rate: 1.2 mL/min; detector UV 220
nm.) Anal. Calcd. for C.sub.27H.sub.29N.sub.3O.su- b.4S*0.2 M
Et.sub.2O containing 1.8% of inorganic impurities, %: C, 64.75; H,
6.06; N, 8.15. Found, %: C, 64.76; H, 6.07; N, 8.19.
EXAMPLE 64
(E)-N-Hydroxy-3-[3-({4-[2-(2naphthyl)ethyl]-1-piperazinyl}sulfonyl)phenyl]-
-2-propenamide (PX118914)
[0975] The title compound was obtained using methods analogous to
those described above. M.p. 184.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO), .delta.: 2.38-3.07 (12H, m, partly
overlapped with a signal of DMSO); 6.63 (1H, d, J=16.0 Hz);
7.20-7.54 (4H, m); 7.57-7.98 (8H, m); 9.16 (1H, br s); 10.78 ppm
(1H, br s). HPLC analysis on Alltima C.sub.18: impurities 1.0%
(column size 4.6.times.150 mm; mobile phase acetonitrile-0.1 M
phosphate buffer (pH 2.5), 35:65; sample concentration 1.0 mg/ml;
flow rate 1.2 mL/min; detector UV 220 nm). Anal. Calcd. for
C.sub.25H.sub.27N.sub.3O.sub.4S, %: C, 64.50; H, 5.85; N, 9.03.
Found, %: C, 64.34; H, 5.74; N, 9.02.
EXAMPLE 65
3-(4-Chlorosulfonylphenyl)acrylic Acid (8)
[0976] To neat chlorosulfonic add (26.5 mL, 0.4 mol) at 18.degree.
C. temperature slowly cinnamic acid (7)(7.35 g, 0.05 mol) was
added. As the reaction proceeded, hydrogen chloride gas evolved.
The reaction mixture was stirred successively at 20.degree. C. for
3 hours and at 42.degree. C. for 3 hours. The dark, viscous syrup
was poured into ice water, and the precipitated solid was filtered
and washed with water. The title compound was obtained (6.8 g, 55%)
as a white solid. .sup.1H NMR (DMSO-d.sub.6, HMDSO), .delta.: 6.55
(1H, d, J=16.0 Hz); 7.58 (1H, d, J=16.0 Hz); 7.65 (4H, s); 8.15
(1H, br s).
EXAMPLE 66
(E)-3-[4-({4-[3-(Trifluoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2--
propenoic Acid (9a)
[0977] To a suspension of
1-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)pip- erazine
hydrochloride (0.43 g, 1.62 mmol) in dioxane (5 mL) a solution of
NaHCO.sub.3 (0.27 g, 3.24 mmol) in water (4 mL) and a solution of
3-(4-chlorosulfonyl-phenyl)-acrylic acid (8) (0.40 g, 1.62 mmol)
were added and the resultant mixture was stirred at ambient
temperature for 20 hours. The reaction mixture was poured into
water (50 mL) and the pH of the medium was brought to .about.4 with
2 N HCl. The precipitated solid was filtered, washed with water,
and dried in vacuum to give the title compound (0.59 g, 82%).
.sup.1H NMR (DMSO-d.sub.6, HMDSO), .delta.: 2.96-3.67 (8H, m,
overlapped with a signal of water); 6.74 (1H, d, J=16.3 Hz);
7.01-7.57 (4H, m); 7.67 (1H, d, J=16.3 Hz); 7.82 (2H, d, J=8.4 Hz);
8.00 (2H, d, J=8.4 Hz); 12.71 (1H, brs).
EXAMPLE 67
(E)-3-[4-({4-[Bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-2--
propenoic Acid (9b)
[0978] To a suspension of 1-bis(4-fluorophenyl)methyl piperazine
(0.47 g, 1.62 mmol) in dioxane (5 mL) a solution of NaHCO.sub.3
(0.27 g, 3.24 mmol) in water (4 mL) and a solution of
3-(4-chlorosulfonyl-phenyl)-acryl- ic acid (8) (0.40 g, 1.62 mmol)
were added and the resultant mixture was stirred at ambient
temperature for 20 hours. The reaction mixture was poured into
water (50 mL), the pH of the medium was brought to .about.4 with 2
N HCl, and extracted with ethyl acetate. The extract was washed
successively with water, brine, and dried (Na.sub.2SO.sub.4). The
solvent was removed and the crude product was crystallized from
dioxane to give the title compound (0.58 g, 63%) as a white solid.
.sup.1H NMR (DMSO-d.sub.6, HMDSO), .delta.: 2.19-2.50 (4H, m,
overlapped with a signal of DMSO); 2.80-3.12 (4H, m); 4.42 (1H, s);
6.78 (1H, d, J=16.0 Hz); 7.11 (4H, t, J=9.0 Hz); 7.41 (4H, dd,
J=8.6 and 5.6 Hz); 7.72 (1H, d, J=16.0 Hz); 7.78 (2H, d, J=8.2 Hz);
8.00 (2H, d, J=8.2 Hz); 12.68 (1H, br s).
EXAMPLE 68
(E)-3-[4-({4-[3-(Trifluoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2--
propenoyl Chloride (10a)
[0979] To a suspension of
(E)-3-[4-({4-[3-(trifluoromethyl)phenyl]-1-piper-
azinyl}sulfonyl)phenyl]-2-propenoic acid (9a) (0.30 g, 0.69 mmol)
in dichloromethane (7 mL) oxalyl chloride (0.2 mL, 2.4 mmol) and a
drop of dimethylformamide were added. The reaction mixture was
stirred at ambient temperature for 0.5 hours and at 42.degree. C.
for 1 hour. The reaction mixture was evaporated and the residue was
dried in vacuum to give
(E)-3-[4-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-
-propenoyl chloride (10a) (0.31 g) in a form of a crude
product.
EXAMPLE 69
(E)-3-[4-({-[Bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-2-p-
ropenoyl Chloride (10b)
[0980] To a solution of
(E)-3-[4-({4-[bis(4-fluorophenyl)methyl]-1-piperaz-
inyl}sulfonyl)phenyl]-2-propenoic acid (9b) (0.25 g, 0.5 mmol) in
dichloromethane (7 mL) oxalyl chloride (0.15 mL, 1.75 mmol) and a
drop of dimethylformamide were added. The reaction mixture was
stirred at ambient temperature for 1 hour, then the mixture was
evaporated and the residue was dried in vacuum to give
(E)-3-[4-({[bis(4-fluorophenyl)methyl]-1-pipe-
razinyl}sulfonyl)phenyl]-2-propenoyl chloride (10b) (0.26 g) in a
form of a crude product.
EXAMPLE 70
(E)-N-Hydroxy-3-[4-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}-sulfonyl-
)phenyl]-2-propenamide (PX118937)
[0981] To a suspension of hydroxylamine hydrochloride (0.24 g, 3.4
mmol) in tetrahydrofuran (5.0 mL) a solution of NaHCO.sub.3 (0.40
g, 4.8 mmol) in water (6 mL) was added and the resultant mixture
was stirred at ambient temperature for 5 minutes. The reaction
mixture was added to a suspension of
(E)-3-[4-({-[3-(trifluoromethyl)phenyl]-1-piperazinyl}sulfo-
nyl)phenyl]-2-propenoyl chloride (10a) (0.31 g) in tetrahydrofuran
(5 mL) and the mixture was stirred at ambient temperature for 0.5
hours. The mixture was poured into water (25 mL), the precipitate
was filtered, washed with water, ether, and dried to give the title
compound (0.23 g, 73%). M.p. 178-179.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO), .delta.: 2.95-3.10 (4H, m); 3.23-3.40 (4H,
m, overlapped with a signal of water); 6.62 (1H, d, J=15.9 Hz);
7.09 (1H, d, J=7.7 Hz); 7.16 (1H, s); 7.19 (1H, d, J=8.0 Hz); 7.40
(1H, t, J=7.7 Hz); 7.54 (1H, d, J=15.9 Hz); 7.80 (2H, d, J=8.4 Hz);
7.83 (2H, d, J=8.4 Hz); 9.35 (1H, br s); 10.72 (1H, br s). HPLC
analysis on Omnispher 5 C.sub.18 column: impurities 3.5% (column
size 4.6.times.150 mm; mobile phase acetonitrile-0.1M acetate
buffer (pH 5.0), 50:50; sample concentration 1 mg/ml; flow rate 1.3
mL/min; detector UV 254 nm). Anal. Calcd for
C.sub.20H.sub.20F.sub.3N.sub.3O.sub.4S, %: C 52.74, H 4.43, N 9.23,
S 7.04. Found, %: C 52.04, H 4.29, N 8.86, S 7.20.
EXAMPLE 71
(E)-3-[4-({4-[Bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-N--
hydroxy-2-propenamide (PX118965)
[0982] To a suspension of hydroxylamine hydrochloride (0.18 g, 2.5
mmol) in tetrahydrofuran (5.0 mL) a solution of NaHCO.sub.3 (0.30
g, 3.5 mmol) in water (5 mL) was added and the resultant mixture
was stirred at ambient temperature for 5 minutes. The reaction
mixture was added to a solution of
(E)-3-[4-({4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfon-
yl)phenyl]-2-propenoyl chloride (10b) (0.26 g) in tetrahydrofuran
(5 mL) and the obtained mixture was stirred at ambient temperature
for 0.5 hours. The mixture was poured into water (25 mL), extracted
with ethyl acetate, the extract was washed with water, brine, and
dried (Na.sub.2SO.sub.4). The solvent was removed and the residue
was chromatographed on silica gel with chloroform-isopropanol (9:1)
as eluent to give the title compound (0.087 g, 34%). M.p.
125-126.degree. C. .sup.1H NMR (DMSO-d.sub.6, HMDSO), .delta.:
2.26-2.42 (4H, m); 2.81-3.00 (4H, m); 4.39 (1H, s); 6.64 (1H, d,
J=15.8 Hz); 7.07 (4H, t, J=8.6 Hz); 7.37 (4H, dd, J=8.4 and 5.6
Hz); 7.57 (1H, d, J=15.8 Hz); 7.74 (2H, d, J=8.0 Hz); 7.83 (2H, d,
J=8.0 Hz); 9.19 (1H, s); 10.93 (1H, s). HPLC analysis on Alltima
C.sub.18 column: impurities 2% (column size 4.6.times.150 mm;
mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5), 70:30;
sample concentration 1.0 mg/ml; flow rate 1.0 mL/min; detector UV
215 nm). Anal. Calcd for C.sub.26H.sub.25F.sub.2N.sub.3O.sub.-
4S*0.3 Et.sub.2O*0.2 iso-PrOH*0.1 CHCl.sub.3 (an exhaustively dried
material contains all the indicated traces of solvents (PMR)), %: C
59.87, H 5.35, N 7.51, S 5.73. Found, %: C, 59.85; H, 5.36; N,
7.29, S 5.60.
EXAMPLE 72
1-(1,3-Benzodioxol-5-ylmethyl)-4-({-[(E)-3-(hydroxyamino)-3-oxo-1-propenyl-
]phenyl}sulfonyl)piperazin-1-ium Dihydrogen Phosphate
(PX118882)
[0983] The title compound was obtained using methods analogous to
those described above. M.p. 210-211.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO) .delta.: 2.30-2.45 (4H, m, overlapped with a
signal of DMSO); 2.82-2.96 (4H, m); 3.36 (2H, s); 3.89-4.67 (br s,
interchangeable protons); 5.95 (2H, s); 6.62 (1H, d, J=15.8 Hz);
6.68 (1H, d, J=7.8 Hz); 6.77 (1H, s); 6.79 (1H, d, J=7.8 Hz); 7.53
(2H, d, J=15.8 Hz); 7.73 (2H, d, J=8.0 Hz), 7.81 (2H, d, J=8.0 Hz).
HPLC analysis on Omnispher 5 C.sub.18: impurities 2.5% (column size
4.6.times.150 mm; mobile phase acetonitrile-0.1M phosphate buffer
(pH 2.5), 20:80; sample concentration 0.5 mg/ml; flow rate 1.5
ml/min; detector UV 220 nm). Anal. Calcd. for
C.sub.21H.sub.23N.sub.3O.sub.6S*H.sub.3PO.sub.4* 0.25
NaH.sub.2PO.sub.4, %: C 43.98; H, 4.66; N, 7.33, S 5.59. Found, %:
C, 43.59; H, 4.75; N, 7.50, S 5.70.
EXAMPLE 73
(E)-N-Hydroxy-3-(4-{[4-(4-nitorphenyl)-1-piperazinyl]sulfonyl}phenyl)-2-pr-
openamide (PX118918)
[0984] The title compound was obtained using methods analogous to
those described above. M. p. 199-200.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO) .delta.: 2.97-3.09 (4H, m); 3.49-3.62 (4H,
m); 6.61 (1H, d, J=15.7 Hz); 6.99 (2H, d, J=9.2 Hz); 7.52 (1H, d,
J=15.7 Hz); 7.78 (2H, d, J=9.0 Hz); 7.81 (2H, d, J=9.0 Hz); 8.02
(2H, d, J=9.2 Hz); 9.17 (1H, s); 10.91 (1H, s). HPLC analysis on
Omnispher 5 C.sub.18: impurities 3.0% (column size 4.6.times.150
mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5),
40:60; sample concentration 0.25 mg/ml; flow rate 1.5 mL/min;
detector UV 270 nm). Anal. Calcd. for
C.sub.19H.sub.20N.sub.4O.sub.6S, %: C 52.77, H 4.66, N 12.96, S
7.41. Found, %: C, 52.56; H, 4.74; N, 12.41, S 7.28.
EXAMPLE 74
(E)-3-(4-{[4-(2-Fluorophenyl)-1-piperazinyl]sulfonyl}phenyl)-N-hydroxy-2-p-
ropenamide (PX118891)
[0985] The title compound was obtained using methods analogous to
those described above. M.p. 196-197.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO) .delta.: 3.00-3.14 (8H, m); 6.63 (1H, d,
J=15.8 Hz); 6.92-7.18 (4H, m); 7.55 (1H, d, J=15.8 Hz); 7.80 (2H,
d, J=8.6 Hz); 7.84 (2H, d, J=8.6 Hz); 9.16 (1H, s); 10.92 (1H, s).
HPLC analysis on Alltima C.sub.18: impurities 3.5% (column size
4.6.times.150 mm; mobile phase acetonitrile-0.1M phosphate buffer
(pH 2.5), 50:50; sample concentration 1.0 mg/ml; flow rate 1.0
mL/min; detector UV 254 nm.) Anal. Calcd. for
C.sub.19H.sub.20FN.sub.3O.sub.4S*0.2 EtOAc, %: C, 56.21; H, 5.15;
N, 9.93, S 7.58. Found, %: C 56.07, H 5.10, N 9.97, S 7.60.
EXAMPLE 75
(E)-N-Hydroxy-3-(4-{[4-(3-methoxyphenyl)-1-piperazinyl]sulfonyl}phenyl)-2--
propenamide (PX118892)
[0986] The title compound was obtained using methods analogous to
those described above. M.p. 199-200.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO) .delta.: 2.95-3.06 (4H, m); 3.13-3.25 (4H,
m); 3.68 (3H, s); 6.38 (1H, d, J=8.0 Hz); 6.42 (1H, s); 6.47 (1H,
d, J=8.2 Hz); 6.61 (1H, d, J=16.0 Hz); 7.09 (1H, t, J=8.0 Hz); 7.54
(1H, d, J=16.0 Hz); 7.78 (2H, d, J=8.4 Hz); 7.83 (2H, d, J=8.4 Hz);
9.17 (1H, s); 10.91 (1H, br s). HPLC analysis on Omnispher 5
C.sub.18: impurities 4.5% (column size 4.6.times.150 mm; mobile
phase acetonitrile-0.1M phosphate buffer (pH 2.5), 45:55; sample
concentration 0.15 mg/ml; flow rate 1.2 mL/min; detector UV 254
nm). Anal. Calcd. for C.sub.20H.sub.23N.sub.3O.sub.5S*0.1
EtOAc*0.2H.sub.2O, %: C, 57.00; H, 5.67; N, 9.77, S 7.46. Found, %:
C, 57.04; H, 5.52; N, 9.64, S 7.38.
EXAMPLE 76
(E)-N-Hydroxy-3-(4-{[4-(2-methoxyphenyl)-1-piperazinyl]sulfonyl}phenyl)-2--
propenamide (PX118905)
[0987] The title compound was obtained using methods analogous to
those described above. M.p. 225-226.degree. C., .sub.1H NMR
(DMSO-d.sub.6, HMDSO) .delta. 2.89-3.13 (8H, m); 3.70 (3H, s); 6.63
(1H, d, J=15.8 Hz); 6.83-7.00 (4H, m); 7.56 (1H, d, J=15.8 Hz);
7.80 (2H, d, J=8.2 Hz); 7.85 (2H, d, J=8.2 Hz); 9.18 (1H, br s);
10.93 (1H, br s). HPLC analysis on Omnispher 5 C.sub.18: impurities
4.5%. (column size 4.6.times.150 mm; mobile phase acetonitrile-0.1M
phosphate buffer (pH 2.5), 40:60; sample concentrafon 0.2 mg/ml;
flow rate 1.2 mL/min; detector UV 254 nm). Anal. Calcd. for
CaoH23N.sub.3O.sub.5S*0.2 EtOAc*0.2H.sub.2O, %: C 56.95, H 5.74, N
9.58, S 7.31. Found, %: C, 56.95; H, 5.66; N, 9.40, S 7.54.
EXAMPLE 77
3-{4-[4-(3-Chloro-phenyl)-piperazine-1-sulfonyl]-phenyl}-N-hydroxy-acrylam-
ide (PX118906)
[0988] The title compound was obtained using methods analogous to
those described above.
EXAMPLE 78
N-Hydroxy-3-[4-(4-pyrimidin-2-yl-piperazine-1-sulfonyl)-phenyl]-acrylamide
(PX118907)
[0989] The title compound was obtained using methods analogous to
those described above.
EXAMPLE 79
3-[4-(4-Benzhydryl-piperazine-1-sulfonyl)-phenyl-N-hydroxy-acrylamide
(PX118910)
[0990] The title compound was obtained using methods analogous to
those described above.
EXAMPLE 80
N-Hydroxy-3-[4-(3-methyl-4-m-tolyl-piperazine-1-sulfonyl)-phenyl]-acrylami-
de (PX118911)
[0991] The title compound was obtained using methods analogous to
those described above.
[0992] Method E--General Synthesis of 1-Acylpiperazines
[0993] Appropriate carboxylic acid (1-2 mmol) and
hydroxybenztriazole (1 eq) were suspended in chloroform (2 mL/1
mmol) and a solution of 1,3-dicylcohexylcarbodiimide (DCC) (1 eq)
in a minimal amount of dimethylformamide was added. The mixture was
stirred for 30 minutes at room temperature to give white
suspension. The mixture was transferred slowly to a pre-cooled
solution of anhydrous piperazine (5 eq) in chloroform (1 mL/1
mmol). The reaction was stirred for 4 hours at room temperature,
the white suspension (DCU) was filtered, and the filtrate was
extracted with 2 M HCl. The HCl extracts were basified with 2 M
NaOH to pH 9, extracted with ethyl acetate, and the organic extract
was washed with brine, dried (Na.sub.2SO.sub.4), and evaporated
under reduced pressure. The crude product was used without further
purification, or was purified on silica gel (20 g) with
methanol-NH.sub.4OH (ca. 95:5 to 90:10) as eluent.
EXAMPLE 81
2-Naphthyl(1-piperazinyl)methanone (13a)
[0994] The title compound was prepared from naphthalene
2-carboxylic acid (12a), using Method E, yield 94%. .sup.1H NMR
(CDCl.sub.3, HMDS), o: 1.92(s, 1H); 2.87(t, J=5.0 Hz, 4H); 3.63(t,
J=5.0 Hz, 4H); 7.43-7.74(m, 3H); 7.89-8.12(m, 4H).
EXAMPLE 82
2-(5-Methoxy-1H-indol-3-yl)-1-(1-piperazinyl)-1-ethanone (13b)
[0995] The title compound was prepared from
2-(5-methoxy-1H-indol-3-yl)ace- tic acid (12b), using Method E,
yield 75%. .sup.1H NMR (CDCl.sub.3, HMDS), .delta.: 1.61(s, 1H);
2.63(t, J=5.0 Hz, 2H); 2.78(t, J=5.0 Hz, 2H); 3.45(t, J=5.0 Hz,
2H); 3.65(t, J=5.0 Hz, 2H); 3.78(s, 2H); 3.83(s, 3H); 6.78(dd,
J=8.8 and 3.0 Hz, 1H); 7.06(t, J=3.0 Hz, 2H); 7.22(d, J=8.8 Hz,
1H); 8.27(s, 1H).
EXAMPLE 83
2-(2-Naphthyloxy)-1-(1-piperazinyl)-1-ethanone (13c)
[0996] The title compound was prepared from 2-(2-naphthyloxy)acetic
acid (2c), using Method E, yield 97%. .sup.1H NMR (CDCl.sub.3,
HMDS), .delta.: 1.69(s, 1H); 2.83(t, J=5.0 Hz, 4H); 3.61(t, J=5.0
Hz, 4H); 4.81(s, 2H); 7.12-7.58(m, 4H); 7.69-7.92(m, 3H).
EXAMPLE 84
2-(1-Naphthyloxy)-1-(1-piperazinyl)-1-ethanone (13d)
[0997] The title compound was prepared from 2-(1-naphthyloxy)acetic
acid (2d), using Method E, yield 82%. .sup.1H NMR (CDCl.sub.3,
HMDS), .delta.: 1.87(s, 1H); 2.63(t, J=5.0 Hz, 2H); 2.83(t, J=5.0
Hz, 2H); 3.45(t, J=5.0 Hz, 2H); 3.65(t, J=5.0 Hz, 2H); 3.89(s, 2H);
7.29-7.61(m, 3H); 7.65-7.96(m, 4H).
EXAMPLE 85
2-(1-Benzothiophen-3-yl)-1-(1-piperazinyl)-1-ethanone (13e)
[0998] The title compound was prepared from
2-(1-benzothiophen-3-yl)acetic acid (12e), using Method E, yield
92%. .sup.1H NMR (CDCl.sub.3, HMDS), .delta.: 1.61(s, 1H); 2.67(t,
J=5.0 Hz, 2H); 2.83(t, J=5.0 Hz, 2H); 3.43(t, J=5.0 Hz, 2H);
3.67(t, J=5.0 Hz, 2H); 3.81(s, 2H); 7.21-7.54(m, 3H); 7.69-7.98(m,
2H).
EXAMPLE 86
3-(1H-indol-3-yl)-1-(1-piperazinyl)-1-propanone (13f)
[0999] The title compound was prepared from
3-(1H-indol-3-yl)propanoic acid (12f), using Method E, yield 79%.
.sup.1H NMR (CDCl.sub.3, HMDS), .delta.: 2.03(s, 1H); 2.54-2.89(m,
6H); 3.03-3.21(m, 2H); 3.34(t, J=5.0 Hz, 2H); 3.58(t, J=5.0 Hz,
2H); 7.00-7.45(m, 4H); 7.52-7.74(m, 1H); 8.13(bs, 1H).
EXAMPLE 87
1H-Indol-3-yl(1-piperazinyl)methanone (13g)
[1000] The title compound was prepared from 1H-indole-3-carboxylic
acid (12g), using Method E, yield 39%. .sup.1H NMR (CDCl.sub.3,
HMDS), .delta.: 1.67(s, 1H); 2.89(t, J=5.0 Hz, 4H); 3.69(t, J=5.0
Hz, 4H); 7.09-7.43(m, 4H); 7.63-7.87(m, 1H); 9.27(bs, 1H).
EXAMPLE 88
Tert-butyl 4-benzoyl-1-piperazinecarboxylate (15h)
[1001] To a solution of N-Boc-piperazine (14) (1.00 g, 5.37 mmol)
in dioxane (5 mL), a solution of NaOH (0.50 g, 12.9 mmol) in water
(5 mL) followed by a solution of benzoyl chloride (0.75 mL, 6.44
mmol) in dioxane (2 mL) under vigorous stirring were added. The
reaction mixture was stirred at ambient temperature for 4 hours,
diluted with brine (20 mL), and extracted with ethyl acetate
(2.times.25 mL). The organic extract was washed successively with
brine (20 mL), saturated NaHCO.sub.3 (20 mL), saturated
KH.sub.2PO.sub.4 (20 mL), and dried (Na.sub.2SO.sub.4). The
solvents were evaporated to give the title compound (1.400 g, 90%)
which was used in the next step of the synthesis without further
purification. .sup.1H NMR (CDCl.sub.3, HMDS), .delta.: 1.41(s, 9H),
2.86(t, J=5.0 Hz, 4H); 3.62(t, J=5.0 Hz, 4H); 7.34(s, 5H).
[1002] Method F--General Synthesis of Tert-Butyl
1-Piperazinecarboxylates
[1003] A solution of appropriate acid 12i-k (2.75 mmol) in
anhydrous dimethylformamide (4.5 mL) was cooled in ice bath under
argon and carbonyldiimidazole (0.490 g, 3.01 mmol) was added. The
mixture was stirred for 30 minutes, then a solution of
N-Boc-piperazine 14 (2.75 mmol) in dimethylformamide (3 mL) was
added. The mixture was stirred at ice bath temperature for 1 hour,
followed by 20 hours at room temperature, diluted with brine (20
mL), and extracted with ethyl acetate (3.times.25 mL). The organic
phase was washed successively with brine (20 mL), saturated
KH.sub.2PO.sub.4 (20 mL), brine (20 mL), and dried
(Na.sub.2SO.sub.4). The solvent was evaporated and the crude
product was used in a further step of the synthesis without
additional purification, or was purified on silica gel (20 g) with
ethyl acetate as eluent.
EXAMPLE 89
tert-Butyl 4-[4-(dimethylamino)benzoyl]-1-piperazinecarboxylate
(15i)
[1004] The title compound was prepared from
4-(dimethylamino)benzoic acid (12), using Method F, yield 61%.
.sup.1H NMR (CDCl.sub.3, HMDS), .delta.: 1.45(s, 9H); 2.98(s, 6H);
3.29-3.74(m, 8H); 6.69(d, J=8.8 Hz, 2H); 7.36(d, J=8.8 Hz, 2H).
EXAMPLE 90
tert-Butyl 4-(4-cyanobenzoyl)-1-piperazinecarboxylate (5)
[1005] The title compound was prepared from 4-cyanobenzoic acid
(12j), using Method F, yield 96%. .sup.1H NMR (CDCl.sub.3, HMDS),
.delta.: 1.40(s, 9H); 2.87(t, J=5.0 Hz, 4H); 3.63(t, J=5.0 Hz, 4H);
6.70(d, J=8.8 Hz, 2H); 7.12(d, J=8.8 Hz, 2H).
EXAMPLE 91
tert-Butyl
4-{2-[4-(dimethylamino)phenyl]acetyl}-1-piperazinecarboxylate
(15k)
[1006] The title compound was prepared from
2-[4-(dimethylamino)phenyl]ace- tic acid (12k), using Method F,
yield 60%. .sup.1H NMR (CDCl.sub.3, HMDS), o: 1.43(s, 9H); 2.92(s,
6H); 3.07-3.78(m, 8H); 3.65(s, 2H); 6.72(d, J=8.8 Hz, 2H); 7.14(d,
J=8.8 Hz, 2H).
[1007] Method G--General Synthesis of 1-Acylpiperazines
[1008] A solution of an appropriate N-Boc-piperazine derivative
15h-k (2.5 mmol) in 1 N HCl methanol (12.5 mL) (made in situ from
AcCl and MeOH) was stirred for 2 hours at ambient temperature, and
then the mixture was evaporated. To the residue, water (30 mL) was
added, the mixture was washed with diethyl ether, and the pH of the
aqueous phase was brought to 9 with 2 M NaOH. The reaction product
was extracted with chloroform (3.times.25 mL), the organic extract
was washed with brine (25 mL), and dried (Na.sub.2SO.sub.4). The
solvent was evaporated and the crude product was used in a further
step of the synthesis without additional purification, or was
purified on silica gel (20 g) with methanol-NH.sub.4OH (9:1) as
eluent.
EXAMPLE 92
Phenyl(1-piperazinyl)methanone (13h)
[1009] The title compound was prepared from tert-butyl
4-benzoyl-1-piperazinecarboxylate (15h), using Method G, yield 87%.
.sup.1H NMR (CDCl.sub.3, HMDS), .delta.: 1.81(s, 1H); 2.76(t, J=5.0
Hz, 4H); 3.56(bs, 4H); 7.41 (s, 5H).
EXAMPLE 93
[4-(Dimethylamino)phenyl](1-piperazinyl)methanone (13i)
[1010] The title compound was prepared from tert-butyl
4-[4-(dimethylamino)benzoyl]-1-piperazinecarboxylate (15i), using
Method G, yield 82%. .sup.1H NMR (CDCl.sub.3, HMDS), .delta.: 1.91
(s, 1H); 2.87(t, J=5.0 Hz, 4H); 2.98(s, 6H); 3.63(t, J=5.0 Hz, 4H);
6.67(d, J=8.8 Hz, 2H); 7.34(d, J=8.8 Hz, 2H).
EXAMPLE 94
4-(1-Piperazinylcarbonyl)benzonitrile (13j)
[1011] The title compound was prepared from tert-butyl
4-(4-cyanobenzoyl)-1-piperazinecarboxylate (15j), using Method G,
yield 62%. .sup.1H NMR (CDCl.sub.3, HMDS), .delta.: 1.92(s, 1H);
2.69-3.02(m, 4H); 3.14-3.92(m, 4H); 7.49(d, J=8.8 Hz, 2H); 7.72(d,
J=8.8 Hz, 2H).
EXAMPLE 95
8-(4-{2-[4-Dimethylamino)phenyl]acetyl}-1-piperazinyl)-N-hydroxy-8-oxoocta-
namide (13k)
[1012] The title compound was prepared from tert-butyl
4-{2-[4-dimethylamino)phenyl]acetyl}-1-piperazinecarboxylate (15k),
using Method G, yield 80%. .sup.1H NMR (CDCl.sub.3, HMDS), .delta.:
1.63(s, 1H); 2.63(t, J=5.0 Hz, 2H); 2.78(t, J=5.0 Hz, 2H); 2.92(s,
6H); 3.41(t, J=5.0 Hz, 2H); 3.58(t, J=5.0 Hz, 2H); 3.65(s, 2H);
6.99(d, J=8.8 Hz, 2H); 7.11(d, J=8.8 Hz, 2H).
[1013] Method H--General Synthesis of N-Monosubstituted
Piperazines
[1014] To a suspension of LIAIH.sub.4 (2.5 eq) in anhydrous
tetrahydrofuran (2-3 mL/ 1 mmol) under argon atmosphere, a solution
of appropriate N-acylpiperazine 13b.c,fcg,k (1 eq) in
tetrahydrofuran (1.5 mL/1 mmol) was added, and the mixture was
stirred at reflux temperature until the initial compound
disappeared (3-7 hours on average). The reaction mixture was
allowed to cool to room temperature and methanol, water, and 1 N
NaOH were carefully added. The reaction mixture was stirred for 2
hours at room temperature and the mixture passed through a celite
pad. The filtrate was evaporated and the residue was purified on
silica gel (20 g) with methanol-NH.sub.4OH (9:1) as eluent to give
the expected piperazine product.
EXAMPLE 96
5-Methoxy-3-[2-(1-piperazinyl)ethyl]-1H-indole (16b)
[1015] The title compound was prepared from
2-(5-Methoxy-1H-indol-3-yl)-1-- (1-piperazinyl)-1-ethanone (13b),
using Method H, yield 38%. .sup.1H NMR (CDCl.sub.3, HMDS), .delta.:
1.61(s, 1H); 2.47-2.81 (m, 6H); 2.87-3.09(m, 6H); 3.85(s, 3H);
6.85(dd, J=8.8 and 3.0 Hz, 1H); 7.05(t, J=3.0 Hz, 2H); 7.25(d,
J=8.8 Hz, 1H); 7.83(s, 1H).
EXAMPLE 97
1-[2-(2-Naphthyloxy)ethyl]piperazine (16c)
[1016] The title compound was prepared from
2-(2-naphthyloxyyl-(1-piperazi- nylyl-ethanone (13c), using Method
H, yield 43%. .sup.1H NMR (CDCl.sub.3, HMDS), .delta.: 1.48(s, 1H);
2.56(t, J=5.0 Hz, 4H); 2.85(t, J=6.0 Hz, 2H); 2.92(t, J=5.0 Hz,
4H); 4.25(t, J=6.0 Hz, 2H); 7.05-7.58(m, 4H); 7.65-7.89(m, 3H).
EXAMPLE 98
3-[3-(1-piperazinyl)propyl]-1H-indole (6
[1017] The title compound was prepared from
3-(1H-indol-3-yl)-1-(1-piperaz- inyl)I-propanone (13f), using
Method H, yield 74%. .sup.1H NMR (DMSO, HMDS), .delta.: 1.69(t,
J=7.0 Hz, 1H); 1.78(t, J=7.0 Hz, 1H); 2.12-2.34(m, 6H);
2.36-2.47(1H, overlapped with DMSO signal); 2.49-2.76(m, 6H);
6.67-7.00(m, 3H); 7.05-7.45(m, 2H); 10.49(s, 1H).
EXAMPLE 99
3-(1-Piperazinylmethyl)-1H-indole (16g)
[1018] The title compound was prepared from
1H-indol-3-yl(1-piperazinyl)me- thanone (13g), using Method H,
yield 63%. .sup.1H NMR (CDCl.sub.3, HMDS), .delta.: 1.81(s, 1H);
2.49(t, J=5.0 Hz, 4H); 2.89(t, J=5.0 Hz, 4H); 3.72(s, 2H);
7.05-7.52(m, 4H); 7.65-7.83(m, 1H); 8.14(bs, 1H).
EXAMPLE 100
N,N-Dimethyl-4-[2-(1-piperazinyl)ethyl]aniline (16k)
[1019] The title compound was prepared from
8-(4-{2-[4-(dimethylamino)phen-
yl]acetyl}-1-piperazinyl)-N-hydroxy-8-oxooctanamide (13k), using
Method H, yield 82%. .sup.1H NMR (CDCl.sub.3, HMDS), .delta.:
1.74(s, 1H); 2.34-2.72(m, 8H); 2.89(s, 6H); 2.81-3.03(m, 4H);
6.72(d, J=8.8 Hz, 2H); 7.09(d, J=8.8 Hz, 2H).
[1020] Method J--General Synthesis of Amidoesters
[1021] A solution of dicarbonic acid monoethyl (or monomethyl)
ester 18a or 18b (2.73 mmol) in anhydrous tetrahydrofuran (5 mL)
under argon atmosphere was cooled in an ice bath and to the
solution carbonyldiimidazole (0.500 g, 3.08 mmol) was added. The
mixture was stirred for 1 hour at ice bath temperature, then
appropriate piperazine (2.73 mmol) was added. The reaction mixture
was stirred at room temperature for 20 hours, concentrated under
vacuum, and partitioned between brine (30 mL) and ethyl acetate (40
mL). The organic layer was washed successively with water (25 mL),
5% citric acid (25 mL), brine (25 mL), and dried (MgSO.sub.4). The
solvent was evaporated and the residue was chromatographed on
silica gel (20 g) with petroleum ether-ethyl acetate as eluent
affording the corresponding reaction product.
EXAMPLE 101
8-Oxo-8-(4-phenyl-piperazin-1-yl)-octanoic Acid Methyl Ester
(19a)
[1022] The title compound was obtained from suberic acid monomethyl
ester (18b) and N-phenylpiperazine (17a) (commercially available)
using Method J, yield 88%. .sup.1H NMR (DMSO-d.sub.6, HMDSO),
.delta.: 1.05-1.72 (m, 8H); 2.02-2.30 (m, 8H); 3.30-3.60 (m, 4H);
3.51 (s, 3H); 7.21-7.51 (m, 5H).
EXAMPLE 102
Ethyl 7-(4-benzhydryl-1-piperazinyl)-7-oxoheptanoate (19b)
[1023] The title compound was obtained from pimelic acid monoethyl
ester (18a) and 1-(diphenylmethyl)piperazine (17b) (commercially
available) using Method J, yield 80%. .sup.1H NMR (DMSO-d.sub.6,
HMDSO), .delta.: 1.04-1.62 (m, 9H); 2.12-2.36 (m, 8H); 3.35-3.50
(m, 4H); 4.17 (q, 2H, J=7.3 Hz); 4.31 (s, 1H); 7.02-7.59 (m,
10H).
EXAMPLE 103
Ethyl 7-oxo-7-(4-phenyl-1-piperazinyl)heptanoate (19c)
[1024] The title compound was obtained from pimelic acid monoethyl
ester (18a) and N-phenylpiperazine (17a) (commercially available)
using Method J, yield 88%. .sup.1H NMR (DMSO-d.sub.6, HMDSO),
.delta.: 1.12-1.62 (m, 9H); 1.97-2.35 (m, 8H); 3.27-3.59 (m, 4H);
4.17 (q, 2H, J=7.2 Hz); 7.03-7.51 (m, 5H).
EXAMPLE 104
Methyl 8-(4-benzhydryl-1-piperazinyl)-8-oxooctanoate (19d)
[1025] The title compound was obtained from suberic add monomethyl
ester (18b and 1-(diphenylmethyl)piperazine (17b) (commercially
available) using Method J, yield 91%. .sup.1H NMR (DMSO-d.sub.6,
HMDSO), .delta.: 1.02-1.67 (m, 8H); 2.09-2.38 (m, 8H); 3.33-3.51
(m, 4H); 3.56 (s, 3H); 4.29 (s, 1H); 7.09-7.56 (m, 10H).
EXAMPLE 105
Methyl 8-[4-(2-methoxyphenyl)-1-piperazinyl]-8-oxooctanoate
(19e)
[1026] The title compound was obtained from suberic acid monomethyl
ester (18b) and 1-(2-methoxyphenyl)piperazine hydrochloride (17c)
(commercially available) (before the addition of hydrochloride
(17c), triethylamine (3.0 mmol) was added to the reaction mixture),
using Method J, yield 87%. .sup.1H NMR (DMSO-d.sub.6, HMDSO),
.delta.: 1.12-1.60 (m, 8H); 1.97-2.82 (m, 8H, overlapped with a
signal of DMSO); 3.40-3.62 (m, 7H); 3.75 (s, 3H); 6.92-7.15 (m,
4H).
[1027] Method K--General Synthesis of Amidoesters
[1028] To a solution of dicarbonic acid monoethyl (or monomethyl)
ester 18a or 18b (2.75 mmol) in anhydrous dichloromethane (10 mL)
oxalyl chloride (0.84 mL, 9.63 mmol) and a drop of
dimethylformamide were added, and the resulting mixture was stirred
for 30 minutes at room temperature followed by 1 hour at 40.degree.
C. The solution was carefully evaporated under reduced pressure and
the residue was dried in vacuum at 40.degree. C.: The resulting
chloride was dissolved in anhydrous tetrahydrofuran (3 mL) and the
obtained solution to a cold suspension (ice bath) of piperazine
(2.75 mmol), tetrahydrofuran (10 mL), and saturated NaHCO.sub.3 (10
mL) under vigorous stirring was added. The stirring was continued
for 1 hour at ice bath temperature and 20 hours at room
temperature. The mixture was diluted with brine (30 mL) and
extracted with ethyl acetate (3.times.25 mL). The organic phase was
washed with brine and dried (Na.sub.2SO.sub.4). The solvent was
evaporated and the residue was chromatographed on silica gel (20 g)
with benzene-ethyl acetate as eluent to give the corresponding
reaction product.
EXAMPLE 106
Ethyl 8-[4-(2-chlorophenyl)-1-piperazinyl]-8-oxooctanoate (19f)
[1029] The title compound was obtained from suberic acid monoethyl
ester (18c) and 1-(2-chlorophenyl)piperazine (17) (commercially
available) using Method K, yield 80%. .sup.1H NMR (CDCl.sub.3,
HMDSO), .delta.: 1.13(t, J=7.0 Hz, 3H); 1.18-1.91(m, 8H); 2.29(t,
J=6.0 Hz, 2H); 2.38(t, J=6.0 Hz, 2H); 3.02(t, J=5.0 Hz, 4H);
3.50-3.90(m, 4H); 4.11 (q, J=7.0 Hz, 2H); 6.85-7.09(m, 2H);
7.14-7.48(m, 2H).
EXAMPLE 107
Ethyl 8-[4-(3-chlorophenyl)-1-piperazinyl]-8-oxooctanoate (19g)
[1030] The title compound was obtained from suberic acid monoethyl
ester (18c) and 1-(3-chlorophenyl)piperazine (17e) (commercially
available) using Method K, yield 88%. .sup.1H NMR (CDCl.sub.3,
HMDSO), .delta.: 1.23(t, J=7.0 Hz, 3H); 1.18-1.79(m, 8H); 2.29(t,
J=6.0 Hz, 2H); 2.36(t, J=6.0 Hz, 2H); 3.14(t, J=5.0 Hz, 4H);
3.44-3.87(m, 4H); 4.11(q, J=7.0 Hz, 2H); 6.66-6.92(m, 2H);
7.05-7.37(m, 2H).
EXAMPLE 108
Ethyl 7-[4-(2-chlorophenyl)-1-piperazinyl]-7-oxoheptanoate
(19h)
[1031] The title compound was obtained from pimelic acid monoethyl
ester (18a) and 1-(2-chlorophenyl)piperazine (17d) (commercially
available) using Method K, yield 79%. .sup.1H NMR (CDCl.sub.3,
HMDSO), .delta.: 1.23(t, J=7.0 Hz, 3H); 1.18-1.89(m, 6H); 2.29(t,
J=6.0 Hz, 2H); 2.38(t, J=6.0 Hz, 2H); 3.00(t, J=5.0 Hz, 4H);
3.49-3.89(m, 4H); 4.12(q, J=7.0 Hz, 2H); 6.85-7.09(m, 2H);
7.14-7.48(m, 2H).
EXAMPLE 109
Ethyl 7-[4-(3-chlorophenyl)-1-piperazinyl]-7-oxoheptanoate
(191)
[1032] The title compound was obtained from pimelic acid monoethyl
ester (18a) and 1-(3-chlorophenyl)piperazine (17e) (commercially
available) using Method K, yield 78%. .sup.1H NMR (CDCl.sub.3,
HMDSO), .delta.: 1.23(t, J=7.0 Hz, 3H); 1.18-1.89(m, 6H); 2.29(t,
J=6.0 Hz, 2H); 2.36(t, J=6.0 Hz, 2H); 3.14(t, J=5.0 Hz, 4H);
3.45-3.89(m, 4H); 4.12(q, J=7.0 Hz, 2H); 6.67-6.94(m, 2H);
7.05-7.38(m, 2H).
[1033] Method L--General Synthesis of Amidoesters
[1034] A solution of dicarbonic acid monomethyl (or monoethyl)
ester 18a-c (2.75 mmol) in anhydrous dimethylformamide (3 mL) was
cooled in ice bath under argon atmosphere and carbonyldiimidazole
(490 mg, 3.01 mmol) was added. The mixture was stirred at Ice bath
temperature for 30 minutes and a solution of appropriate piperazine
(2.75 mmol) in dimethylformamide (3 mL) was added (if the
piperazine was used in a hydrochloride form triethylamine (1.0 mL)
before the piperazine hydrochloride to the reaction mixture was
added). The mixture was stirred at ice bath temperature for 1 hour
followed by 20 hours at room temperature. Then the reaction mixture
was diluted with brine (50 mL) and extracted with ethyl acetate
(3.times.25 mL). The organic phase was washed with brine, dried
(Na.sub.2SO.sub.4), and the solvent was evaporated. The residue was
chromatographed on silica gel with appropriate eluent to give the
corresponding reaction product.
EXAMPLE 110
Ethyl 8-[4-(2-naphthoyl)-1-piperazinyl]-8-oxooctanoate (19j)
[1035] The title compound was obtained from suberic acid monoethyl
ester (18c) and 2-naphthyl(1-piperazinyl)methanone (13a) using
Method L, yield 79%. .sup.1H NMR (CDCl.sub.3, HMDSO), .delta.:
1.16(t, J=7.0 Hz, 3H); 1.18-1.65(m, 8H); 2.25(t, J=6.0 Hz, 2H);
2.38(t, J=6.0 Hz, 2H); 3.36-3.65(m, 8H); 4.02(q, J=7.0 Hz, 2H);
7.43-7.74(m, 3H); 7.89-8.12(m, 4H).
EXAMPLE 111
Ethyl 8-(4-benzoyl-1-piperazinyl)-8-oxooctanoate (19k)
[1036] The title compound was obtained from suberic acid monoethyl
ester (18c) and phenyl(1-piperazinyl)methanone (13h) using Method
L, yield 89%. .sup.1H NMR (CDCl.sub.3, HMDSO), .delta.: 1.28(t,
J=7.0 Hz, 3H); 1.14-1.83(m, 8H); 2.16(t, J=7.0 Hz, 2H); 2.23(t,
J=7.0 Hz, 2H); 3.00-3.25(m, 4H); 3.49-3.83(m, 4H); 3.98(q, J=7.0
Hz, 2H); 7.39(s, 5H).
EXAMPLE 112
Ethyl 8-{4-[4(dimethylamino)benzoyl]-1-piperazinyl}-8-oxooctanoate
(191)
[1037] The title compound was obtained from suberic acid monoethyl
ester (18c) and [4-(dimethylamino)phenyl](1-piperazinyl)methanone
(13i) using Method L, yield 81%. .sup.1H NMR (CDCl.sub.3, HMDSO),
.delta.: 1.27(t, J=7.0 Hz, 3H); 1.15-1.88(m, 8H); 2.34(t, J=7.0 Hz,
2H); 2.52(t, J=6.0 Hz, 2H); 2.88(s, 6H); 3.00-3.21(m, 4H);
3.49-3.87(m, 4H); 4.11(q, J=7.0 Hz, 2H); 7.08(d, J=8.8 Hz, 2H);
7.35(s, 5H).
EXAMPLE 113
Ethyl 8-[4-(4-methoxyphenyl)-1-piperazinyl]-8-oxooctanoate
(19m)
[1038] The title compound was obtained from suberic acid monoethyl
ester (c) and 1-(4-methoxyphenyl)piperazine (17f) (commercially
available) using Method L, yield 76%. .sup.1H NMR (CDCl.sub.3,
HMDSO), .delta.: 1.16(t, J=7.0 Hz, 3H); 1.05-1.76(m, 8H); 2.22(t,
J=7.0 Hz, 2H); 2.29(t, J=7.0 Hz, 2H); 2.85-3.07(m, 4H);
3.43-3.78(m, 4H); 3.72(s, 3H); 4.05(q, J=7.0 Hz, 2H); 6.83(s,
4H).
EXAMPLE 114
Ethyl 8-[4-(3-methoxyphenyl)-1-piperazinyl]-8-oxooctanoate
(19n)
[1039] The title compound was obtained from suberic acid monoethyl
ester (18c) and 1-(3-methoxyphenyl)piperazine (17g) (commercially
available) using Method L, yield 62%. .sup.1H NMR (CDCl.sub.3,
HMDSO), .delta.: 1.29(t, J=7.0 Hz, 3H); 1.16-1.85(m, 8H); 2.16(t,
J=7.0 Hz, 2H); 2.22(t, J=7.0 Hz, 2H); 3.00-3.25(m, 4H);
3.49-3.83(m, 4H); 3.65(s, 3H); 3.98(q, J=7.0 Hz, 2H); 6.36-6.67(m,
3H); 7.05-7.23(m, 1H).
EXAMPLE 115
Ethyl 8-[4-(4-nitrophenyl)-1-piperazinyl]-8-oxooctanoate (19)
[1040] The title compound was obtained from suberic acid monoethyl
ester (18c) and 1-(4 nitrophenyl)piperazine (17h) (commercially
available) using Method L, yield 67%. .sup.1H NMR (CDCl.sub.3,
HMDSO), .delta.: 1.23(t, J=7.0 Hz, 3H); 1.07-1.89(m, 8H); 2.29(t,
J=7.0 Hz, 2H); 2.36(t, J=7.0 Hz, 2H); 3.25-3.92(m, 8H); 4.12(q,
J=7.0 Hz, 2H); 6.83(d, J=8.8 Hz, 2H); 8.14(d, J=8.8 Hz, 2H).
EXAMPLE 116
Methyl
8-{4-[2-(5-methoxy-1H-indol-3-yl)acetyl]-1-piperazinyl}-8-oxooctano-
ate (19p)
[1041] The title compound was obtained from suberic acid monomethyl
ester (18b) and 2-(5
methoxy-1H-indol-3-yl)-1-(1-piperazinyl)-1-Ethanone (13b) using
Method L, yield 76%. .sup.1H NMR (CDCl.sub.3, HMDSO), .delta.:
1.12-1.89(m, 8H); 2.29(t, J=7.0 Hz, 4H); 3.09-3.74(m, 8H); 3.65(s,
3H); 3.83(s, 2H); 3.85(s, 3H); 6.89(dd, J=8.8 and 3.0 Hz, 1H);
7.07(t, J=3.0 Hz, 2H); 7.16-7.35(m, 1H); 8.31(bs, 1H).
EXAMPLE 117
Methyl 8-{4-[2-(2-naphthyloxy)ethyl]-1-piperazinyl}-8-oxooctanoate
(19r)
[1042] The title compound was obtained from suberic acid monomethyl
ester (18b) and 1-[2-(2-naphthyloxy)ethyl]piperazine (16c) using
Method L, yield 56%. .sup.1H NMR (CDCl.sub.3, HMDSO), o:
1.14-1.81(m, 8H); 2.29(t, J=7.0 Hz, 4H); 2.43-2.69(m, 4H); 2.87(t,
J=5.0 Hz, 2H); 3.32-3.74(m, 4H); 3.63(s, 3H); 4.23(t, J=5.0 Hz,
2H); 7.03-7.23(m, 2H); 7.29-7.52(m, 2H); 7.61-7.83(m, 2H).
EXAMPLE 118
Ethyl 8-{4-[2-(1-naphthyloxy)acetyl]-1-piperazinyl}-8-oxooctanoate
(19s)
[1043] The title compound was obtained from suberic add monoethyl
ester (18c) and 2-(1-naphthyloxy)-1-(1-piperazinyl)-1-Ethanone
(13d) using Method L, yield 65%. .sup.1H NMR (CDCl.sub.3, HMDSO),
.delta.: 1.23(t, J=7.0 Hz, 3H); 1.18-1.85(m, 8H); 2.27(t, J=7.0 Hz,
4H); 3.10-3.81(m, 8H); 3.92(s, 2H); 4.12(q, J=7.0 Hz, 2H);
7.32-7.59(m, 3H); 7.65-7.94(m, 4H).
EXAMPLE 119
Methyl
8-{4-[2-(5-methoxy-1H-indol-3-yl)ethyl]-1-piperazinyl}-8-oxooctanoa-
te (19t)
[1044] The title compound was obtained from suberic acid monomethyl
ester (18b) and 5-methoxy-3-[2-(1-piperazinyl)ethyl]-1H-indole
(16b) using Method L, yield 89%. .sup.1H NMR (CDCl.sub.3, HMDSO),
.delta.: 1.18-1.78(m, 8H); 2.34(t, J=7.0 Hz, 4H); 2.52(t, J=6.0 Hz,
4H); 2.6-2.89(m, 4H); 3.38-3.74(m, 4H); 3.67(s, 3H); 3.85(s, 3H);
6.87(dd, J=8.8 and 3.0 Hz, 1H); 7.03(t, J=3.0 Hz, 2H); 7.25(d,
J=8.8 Hz, 1H); 8.01(s, 1H).
EXAMPLE 120
Ethyl
8-{4-[2-(1-benzothiophen-3-yl)acetyl]-1-piperazinyl}-8-oxooctanoate
(19u)
[1045] The title compound was obtained from suberic acid monoethyl
ester (18c) and
2-(1-benzothiophen-3-yl)-1-(1-piperazinyl)-1-Ethanone (13e) using
Method L, yield 83%. .sup.1H NMR (CDCl.sub.3, HMDSO), .delta.:
1.23(t, J=7.0 Hz, 3H); 1.16-1.87(m, 8H); 2.29(t, J=7.0 Hz, 4H);
3.27-3.83(m, 8H); 3.94(s, 2H); 4.12(q, J=7.0 Hz, 2H); 7.18-7.52(m,
2H); 7.72-7.96(m, 2H).
EXAMPLE 121
Ethyl 7-[4-(3,4-dichlorophenyl)-1-piperazinyl]-7-oxoheptanoate
(19y)
[1046] The title compound was obtained from pimelic acid monoethyl
ester (18a) and 1-(3,4-dichlorophenyl)piperazine (17i)
(commercially available) using Method L, yield 73%. .sup.1H NMR
(CDCl.sub.3, HMDSO), .delta.: 1.23(t, J=7.0 Hz, 3H); 1.14-1.87(m,
6H); 2.16-2.49(m, 4H); 2.98-3.23(m, 4H); 3.47-3.83(m, 4H); 4.09(q,
J=7.0 Hz, 2H); 6.74(dd, J=8.8 and 3.0 Hz, 1H); 6.96(d, J=3.0 Hz,
1H); 7.32(d, J=8.8 Hz, 1H).
EXAMPLE 122
Ethyl 7-[4-(4-fluorophenyl)-1-piperazinyl]-7-oxoheptanoate
(19v)
[1047] The title compound was obtained from pimelic acid monoethyl
ester (18a) and 1-(4-fluorophenyl)piperazine (17j) (commercially
available) using Method L, yield 74%. .sup.1H NMR (CDCl.sub.3,
HMDSO), .delta.: 1.22(t, J=7.0 Hz, 3H); 1.16-1.89(m, 6H);
2.16-2.49(m, 4H); 2.93-3.18(m, 4H); 3.49-3.87(m, 4H); 4.09(q, J=7.0
Hz, 2H); 6.77-7.14(m, 4H).
EXAMPLE 123
Ethyl 7-[4-(4-chlorophenyl)-1-piperazinyl]-7-oxoheptanoate
(19w)
[1048] The title compound was obtained from pimelic acid monoethyl
ester (18a) and 1-(4-chlorophenyl)piperazine (17k) (commercially
available) using Method L, yield 75%. .sup.1H NMR (CDCl.sub.3,
HMDSO), .delta.: 1.23(t, J=7.0 Hz, 3H); 1.16-1.87(m, 6H);
2.16-2.49(m, 4H); 3.00-3.21(m, 4H); 3.49-3.87(m, 4H); 4.11(q, J=7.0
Hz, 2H); 6.85(d, J=8.8 Hz, 2H); 7.23(d, J=8.8 Hz, 2H).
[1049] Method M--Synthesis of O-Benzylhydroxamate Esters
[1050] To a solution of dicarbonic acid monoethyl (or monomethyl)
ester 18a-c (2.75 mmol) in anhydrous dichloromethane (10 mL) oxalyl
chloride (0.84 mL, 9.63 mmol) and a drop of dimethylformamide were
added, and the resulting mixture was stirred for 30 minutes at room
temperature followed by 1 hour at 40.degree. C. The solution was
carefully evaporated under reduced pressure and the residue was
dried in vacuum at 40.degree. C. The resulting chloride was
dissolved in anhydrous tetrahydrofuran (3 mL) and the obtained
solution to a cold suspension (ice bath) of benzylhydroxylamine
hydrochloride (2.75 mmol), tetrahydrofuran (10 mL), and saturated
NaHCO.sub.3 (10 mL) was added under vigorous stirring. The stirring
was continued for 1 hour at ice bath temperature and 20 hours at
room temperature. The mixture was diluted with brine (30 mL) and
extracted with ethyl acetate (3.times.25 mL). The organic phase was
washed with brine and dried (Na.sub.2SO.sub.4). The solvent was
evaporated and the residue was chromatographed on silica gel (20 g)
with chloroform-ethyl acetate (gradient from 100:0 to 50:50) as
eluent to give the corresponding reaction product (20a-c) in 80-90%
yield.
EXAMPLE 124
Ethyl 7-[(benzyloxy)amino]-7-oxoheptanoate (20a)
[1051] The title product was obtained from heptanedioic acid
monoethyl ester, using Method M. .sup.1H NMR (CDCl.sub.3, HMDSO),
.delta.: 1.22(t, J=7.0 Hz, 3H); 1.07-1.88(m, 6H); 1.89-2.26(m, 2H);
2.29(t, J=7.0 Hz, 2H); 4.11(q, J=7.0 Hz, 2H); 4.88(s, 2H); 7.31(s,
5H).
EXAMPLE 125
Methyl 8-[(benzyloxy)amino]-8-oxooctanoate (20b)
[1052] The title product was obtained from octanedioic acid
monomethyl ester, using Method M. .sup.1H NMR (CDCl.sub.3, HMDSO),
.delta.: 1.09-1.83(m, 8H); 1.87-2.27(m, 2H); 2.27(t, J=7.0 Hz, 2H);
3.63(s, 3H); 4.87(s, 2H); 7.29(s, 5H).
EXAMPLE 126
Ethyl 8-[(benzyloxy)amino]-8-oxooctanoate (20c)
[1053] The title product was obtained from octanedioic acid
monoethyl ester, using Method M. .sup.1H NMR (CDCl.sub.3, HMDSO),
.delta.: 1.23(t, J=7.0 Hz, 3H); 1.09-1.83(m, 8H); 1.87-2.27(m, 2H);
2.27(t, J=7.0 Hz, 2H); 4.12(q, J=7.0 Hz, 2H); 4.87(s, 2H); 7.29(s,
5H).
[1054] Method N--Synthesis of O-Benzylhydroxamate Carboxylic
Acids
[1055] To a solution of appropriate ester 20a-c (1,5-2 mmol) in
tetrahydrofuran (5 mL), a saturated aqueous solution of LiOH (5 mL)
was added. The mixture was stirred for 5 hours at room temperature.
The organic volatiles were evaporated under reduced pressure and
the mixture was supplemented with water (20 mL). The mixture was
washed with diethyl ether and aqueous phase was acidified with 2 M
HCl to pH 3. The crude product was extracted with ethyl acetate
(3.times.20 mL). The organic layer was washed with brine
(3.times.10 mL) and dried (Na.sub.2SO.sub.4). The solvent was
evaporated and the residue was dried in vacuum to give expected
product 21a or 21 b in 60-70% yield.
EXAMPLE 127
7-[(Benzyloxy)amino]-7-oxoheptanoic Acid (21a),
[1056] The title product was obtained from ethyl
7-[(benzyloxy)amino]-7-ox- oheptanoate (20a), using Method N.
.sup.1H NMR (CDCl.sub.3, HMDSO), .delta.: 1.07-1.88(m, 6H);
1.89-2.26(m, 2H); 2.29(t, J=7.0 Hz, 2H); 4.88(s, 2H); 7.32(s,
5H).
EXAMPLE 128
8-[(Benzyloxy)amino]-8-oxooctanoic Acid (21 b),
[1057] The title product was obtained from methyl
8-[(benzyloxy)amino]-8-o- xooctanoate (20b) or ethyl
8-[(benzyloxy)amino]-8-oxooctanoate (20c), using Method N. .sup.1H
NMR (CDCl.sub.3, HMDSO), .delta.: 1.09-1.81 (m, 8H); 1.88-2.29(m,
2H); 2.27(t, J=7.0 Hz, 2H); 4.86(s, 2H); 7.30(s, 5H).
[1058] Method P--General Synthesis of O-Benzyl Hydroxamates
[1059] A solution of dicarbonic acid N-benzyloxy monoamide 21a or
21 b (1 eq) in anhydrous dimethylformamide (2 mL/mmol) was cooled
in ice bath under argon atmosphere, and carbonyldiimidazole (1.1
eq.) was added. The mixture was stirred at ice bath temperature for
30 minutes and a solution of appropriate piperazine (1 eq) in
dimethylformamide (2 mL/mmol) was added (if the piperazine was used
in a hydrochloride form, triethylamine (3 eq) was added to the
reaction mixture prior to the piperazine hydrochloride). The
mixture was stirred at ice bath temperature for 1 hour followed by
20 hours at room temperature. Then the reaction mixture was diluted
with brine and extracted with ethyl acetate. The organic phase was
washed with brine, dried (Na.sub.2SO.sub.4), and the solvent was
evaporated. The residue was chromatographed on silica gel with
appropriate eluent (chloroform-ethyl acetate for less polar and
ethyl acetate-methanol for more polar compounds) to give the
corresponding reaction product 22a-k.
EXAMPLE 129
N-(Benzyloxy)-8-[4-(4-cyanobenzoyl)-1-piperazinyl]-8-oxooctanamide
(22a)
[1060] The title compound was obtained from
8-[(benzyloxy)amino]-8-oxoocta- noic acid (21b) and
4-(1-piperazinylcarbonyl)benzonitrile (13j), using Method P, yield
79%. .sup.1H NMR (CDCl.sub.3, HMDSO), .delta.: 1.09-1.81(m, 8H);
1.87-2.17(m, 2H); 2.18-2.42(m, 2H); 3.32-3.69(m, 8H); 4.89(s, 2H);
7.38(s, 5H); 7.52(d, J=8.8 Hz, 2H); 7.76(d, J=8.8 Hz, 2H); 8.03(s,
1H).
EXAMPLE 130
N-(Benzyloxy)-7-oxo-7-[4-(2-pyridinyl)-1-piperazinyl]heptanamide
(22b)
[1061] The title compound was obtained from
7-[(benzyloxy)amino]-7-oxohept- anoic acid (21a) and
1-(2-pyridinyl)piperazine (71) (commercially available), using
Method P, yield 50%. .sup.1H NMR (CDCl.sub.3, HMDSO), .delta.:
1.16-1.81(m, 6H); 2.36(t, J=7.0 Hz, 2H); 3.21(q, J=6.0 Hz, 2H);
3.36-3.85(m, 8H); 4.76(bs, 1H); 5.09(s, 2H); 6.58-6.74(m, 2H);
7.34(s, 5H); 7.41-7.63(m, 1H); 8.12-8.29(m, 1H).
EXAMPLE 131
N-(Benzyloxy)-8-(4-{2-[4-(dimethylamino)phenyl]acetyl}-1-piperazinyl)-8-ox-
ooctanamide (22c)
[1062] The title compound was obtained from
8-[(benzyloxy)amino]-8-oxoocta- noic acid (21b) and
2-[4-(dimethylamino)phenyl]-1-(1-piperazinyl)-1-Ethano- ne (13k),
using Method P, yield 68%. .sup.1H NMR (CDCl.sub.3, HMDSO),
.delta.: 1.05-1.81(m, 8H); 1.85-2.32(m, 4H); 2.89(s, 6H);
3.07-3.69(m, 8H); 3.65(s, 2H); 4.87(s, 2H); 6.67(d, J=8.8 Hz, 2H);
7.07(d, J=8.8 Hz, 2H); 7.36(s, 5H); 8.00(s, 1H).
EXAMPLE 132
N-(Benzyloxy)-8-oxo-8-[4-(2-pyrimidinyl)-1-piperazinyl]octanamide
(22d)
[1063] The title compound was obtained from
8-[(benzyloxy)amino]-8-oxoocta- noic acid (21 b and
2-(1-piperazinyl)pyrimidine (17m) (commercially available), using
Method P, yield 64%. .sup.1H NMR (CDCl.sub.3, HMDSO), .delta.:
1.14-1.81(m, 8H); 1.96-2.25(m, 2H); 2.36(t, J=7.0 Hz, 2H);
3.43-3.94(m, 8H); 4.89(s, 2H); 6.54(t, J=5.0 Hz, 1H); 7.38(s, 5H);
7.92-8.03(m, 1H); 8.32(d, J=5.0 Hz, 2H).
EXAMPLE 133
N-(Benzyloxy)-8-(4-{3-[3-(dimethylamino)phenyl]propyl)-1-piperazinyl}-8-ox-
ooctanamide (22e)
[1064] The title compound was obtained from
8-[(benzyloxy)amino]-8-oxoocta- noic acid (2 b) and
N,N-dimethyl-3-[3-(1-piperazinyl)propyl]aniline (16k), using Method
P, yield 63%. .sup.1H NMR (CDCl.sub.3, HMDSO), .delta.:
1.18-1.83(m, 8H); 2.07-2.38(m, 4H); 2.43-2.76(m, 8H); 2.92(s, 6H);
3.38-3.80(m, 4H); 4.92(s, 2H); 6.71(d, J=8.8 Hz, 2H); 7.12(d, J=8.8
Hz, 2H); 7.41(s, 5H); 8.07-8.36(m, 1H).
EXAMPLE 134
N-(Benzyloxy)-8-{4-[2-(2-naphthyloxy)acetyl]-1-piperazinyl}-8-oxooctanamid-
e (22f)
[1065] The title compound was obtained from
8-[(benzyloxy)amino]-8-oxoocta- noic acid (21 b) and
2-(2-naphthyloxy)-1-(1-piperazinyl)-1-Ethanone (13c), using Method
P, yield 66%. .sup.1H NMR (CDCl.sub.3, HMDSO), .delta.:
1.14-1.76(m, 8H); 1.94-2.40(m, 4H); 3.29-3.74(m, 8H); 4.83(s, 2H);
4.88(s, 2H); 7.07-7.30(m, 3H); 7.36(s, 5H); 7.31-7.58(m, 1H);
7.65-7.92(m, 3H); 8.25(bs, 1H).
EXAMPLE 135
N-(Benzyloxy)-7-{4-[3-(1H-indol-3-yl)propanoyl]-1-piperazinyl}-7-oxoheptan-
amide (22g)
[1066] The title compound was obtained from
7-[(benzyloxy)amino]-7-oxohept- anoic acid (21a) and
3-(1H-indol-3-yl)-1-(1-piperazinyl)-1-propanone (13f), using Method
P, yield 63%. .sup.1H NMR (CDCl.sub.3, HMDSO), .delta.:
1.09-1.85(m, 6H); 1.92-2.41(m, 4H); 2.58-3.00(m, 4H); 3.05-3.72(m,
8H); 4.89(s, 2H); 6.91-7.39(m, 5H); 7.38(s, 5H); 7.52-7.74(m, 1H);
8.25-8.76(m, 1H).
EXAMPLE 136
N-(Benzyloxy)-7-[4-(1H-indol-3-ylcarbonyl)-1-piperazinyl]-7-oxoheptanamide
(22h)
[1067] The title compound was obtained from
7-[(benzyloxy)amino]-7-oxohept- anoic acid (21a) and
1H-indol-3-yl(1-piperazinyl)methanone (13c), using Method P, yield
69%. .sup.1H NMR (CDCl.sub.3, HMDSO), .delta.: 1.14-1.78(m, 6H);
1.87-2.45(m, 4H); 3.34-3.78(m, 8H); 4.87(s, 2H); 7.14-7.54(m, 5H);
7.41(s, 5H); 7.58-7.83(m, 1H); 9.14-9.38(m, 1H).
EXAMPLE 137
N-(Benzyloxy)-7-{4-[3-(1H-indol-3-yl)propyl]-1-piperazinyl}-7-oxoheptanami-
de (22i)
[1068] The title compound was obtained from
7-[(benzyloxy)amino]-7-oxohept- anoic acid (21a) and
3-[3-(1-piperazinyl)propyl]-1H-indole (16f), using Method P, yield
87%. .sup.1H NMR (CDCl.sub.3, HMDSO), .delta.: 1.14-2.00(m, 8H);
2.12-2.56(m, 8H); 2.67-2.96(m, 4H); 3.32-3.71(m, 4H); 4.89(s, 2H);
6.92-7.36(m, 5H); 7.38(s, 5H); 7.49-7.69(m, 1H); 7.85-8.00(m,
1H).
EXAMPLE 138
N-(Benzyloxy)-7-[4-(1H-indol-3-ylmethyl)-1-piperazinyl]-7-oxoheptanamide
(22j)
[1069] The title compound was obtained from
7-[(benzyloxy)amino]-7-oxohept- anoic acid (21a) and
3-(1-piperazinylmethyl)-1H-indole (16g), using Method P, yield 59%.
.sup.1H NMR (CDCl.sub.3, HMDSO), .delta.: 1.16-1.87(m, 6H);
2.03-2.60(m, 8H); 3.32-3.69(m, 4H); 3.72(s, 2H); 4.89(s, 2H);
7.05-7.34(m, 5H); 7.38(s, 5H); 7.60-7.85(m, 1H); 8.03-8.41(m,
1H).
EXAMPLE 139
N-(Benzyloxy)-7-[4-(3,4-dimethylphenyl)-1-piperazinyl]-7-oxoheptanamide
(22k)
[1070] The title compound was obtained from
7-[(benzyloxy)amino]-7-oxohept- anoic acid (21a) and
1-(3,4-dimethylphenyl)piperazine (17n) (commercially available),
using Method P, yield 71%. .sup.1H NMR (CDCl.sub.3, HMDSO),
.delta.: 1.14-1.80(m, 6H); 2.11(s, 3H) 2.16(s, 3H); 2.36-2.49(m,
4H); 3.36-3.85(m, 8H); 4.89(s, 2H); 6.70(dd, J=8.8 and 3.0 Hz, 1H);
6.86(d, J=3.0 Hz, 1H); 7.02(d, J=8.8 Hz, 1H), 7.34(s, 5H).
[1071] Method Q--General Synthesis of Hydroxamic Acids from
Amidoesters
[1072] To a 1 M solution of hydroxylamine hydrochloride in methanol
(5 mL, 5 mmol) a 5 M solution of sodium methylate (1 mL, 5 mmol)
was added, and the precipitate was filtered off. To the filtrate, a
solution of appropriate amidoester (19a-e) (2.47 mmol) in methanol
(3 mL) was added and the resultant mixture was stirred at room
temperature for 24 hours. The mixture was acidified with acetic
acid to pH 5 and the solvent was evaporated. The residue was
extracted with ethyl acetate (50 mL), the extract was washed with
water, brine, and dried (MgSO.sub.4). The extract was filtrated,
concentrated to ca. 5-10 mL, and allowed to crystallize. The
precipitate was filtered, washed with ethyl acetate, and dried in
vacuum to give the corresponding hydroxamic acid.
EXAMPLE 140
8-Oxo-8-(4-phenyl-piperazin-1-yl)-octanoic Acid Hydroxyamide
(PX117402)
[1073] The title compound was obtained from
8-oxo-8-(4-phenyl-piperazin-1-- yl)-octanoic acid methyl ester
(19a) by Method Q, yield 42%. M.p. 134-136.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO), .delta.: 1.16-1.38 (m, 4H); 1.38-1.60 (m,
4H); 1.93 (t, 2H, J=7.4 Hz); 2.33 (t, 2H, J=7.2 Hz); 3.09 (m, 4H);
3.57 (m, 4H); 6.80 (t, 1H, J=7.1 Hz); 6.94 (d, 2H, J=8.0 Hz); 7.22
(t, 2H, J=7.7 Hz); 8.66 (s, 1H); 10.33 (s, 1H). HPLC analysis on
Symmetry C.sub.8 column: impurities 1.3% (column size 3.9.times.150
mm; mobile phase acetonitrile-0.1% H.sub.3PO.sub.4, 30:70; detector
UV 220 nm; sample concentration 0.5 mg/ml; flow rate 1.1 mL/min).
Anal. Calcd for C.sub.18H.sub.27N.sub.3O.sub.3, %: C, 64.84; H,
8.16; N, 12.60. Found, %: C, 64.71; H, 8.20; N, 12.52.
EXAMPLE 141
7-(4-Benzhydryl-piperazin-1-yl)-7-oxo-heptanoic Acid Hydroxyamide
(PX117403)
[1074] The title compound was obtained from ethyl
7-(4-benzhydryl-1-pipera- zinyl)-7-oxoheptanoate (19b) by Method Q,
yield 29%. M.p. 157-159.degree. C. .sup.1H NMR (DMSO-d.sub.6,
HMDSO) .delta.: 1.08-1.32 (m, 2H); 1.35-1.60 (m, 4H); 1.82-2.02 (m,
2H); 2.03-2.40 (m, 6H); 3.23-3.60 (m, 4H overlapped with a water
signal of DMSO); 4.30 (s, 1H); 7.09-7.52 (m, 10H); 8.68 (s, 1H);
10.34 (s, 1H). HPLC analysis on Zorbax Rx-C.sub.18 column:
impurities 1.5% (column size 4.6.times.150 mm; mobile phase
acetonitrile-water, 80:20; detector UV 220 nm; sample concentration
1.0 mg/ml; flow rate 1.0 mL/min). Anal. Calcd for
C.sub.24H.sub.31N.sub.3O.su- b.3, %: C 70.39, H 7.63, N 10.26.
Found, %: C, 70.09; H, 7.67; N, 10.11.
EXAMPLE 142
7-Oxo-7-(4-phenyl-piperazin-1-yl)-heptanoic Acid Hydroxyamide
(PX117404)
[1075] The title compound was obtained from ethyl
7-oxo-7-(4-phenyl-1-pipe- razinyl)heptanoate (19c) by Method Q,
yield 27%. M.p. 107-109.degree. C. .sup.1H NMR (DMSO-d.sub.6,
HMDSO) .delta.: 1.15-1.36 (m, 2H); 1.38-1.60 (m, 4H); 1.93 (t, 2H,
J=7.1 Hz); 2.33 (t, 2H, J=7.3 Hz); 3.09 (m, 4H); 3.58 (m, 4H); 6.80
(t, 1H, J=7.3 Hz); 6.95 (d, 2H, J=8.2 Hz); 7.22 (t, 2H, J=7.9 Hz);
8.69 (s, 1H); 10.35 (s, 1H). HPLC analysis on Zorbax SB-C.sub.18
column: impurities 3% (column size 4.6.times.150 mm; mobile phase
methanol-0.1% H.sub.3PO.sub.4, gradient from 50:50 to 90:10;
detector UV 220 nm; sample concentration 0.55 mg/ml; flow rate 1.5
mL/min). Anal. Calcd for C.sub.17H.sub.25N.sub.3O.sub.3, %: C,
63.93; H, 7.89; N, 13.16. Found, %: C 63.80, H 7.89, N 13.06.
EXAMPLE 143
8-(4-Benzhydryl-piperazin-1-yl)-8-oxo-heptanoic Acid Hydroxyamide
(PX117764)
[1076] The title compound was obtained from methyl
8-(4-benzhydryl-1-piper- azinyl)-8-oxooctanoate (19d) by Method Q,
yield 32%. M.p. 126-129.degree. C. .sup.1H NMR (DMSO-d.sub.6,
HMDSO), .delta.: 1.14-1.30 (m, 4H); 1.34-1.54 (m, 4H); 1.91 (t, 2H,
J=7.3 Hz); 2.15-2.32 (m, 6H); 3.38-3.50 (m, 4H); 4.30 (s, 1H);
7.17-7.50 (m, 10H); 8.66 (s, 1H); 10.32 (s, 1H). HPLC analysis on
Symmetry C.sub.8 column: impurities 3.3% (column size 3.9.times.150
mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5),
50:50; detector UV 220 nm; sample concentration 0.5 mg/ml; flow
rate 1.3 mL/min). Anal. Calcd for C.sub.25H.sub.33N.sub.3O.sub.3,
%: C 70.89, H 7.85, N 9.92. Found, %: C70.81, H 7.63, N 10.11.
EXAMPLE 144
8-[4(2-Methoxy-phenyl)-piperazin-1-yl]-8-oxo-octanoic Acid
Hydroxyamide (PX117768)
[1077] The title compound was obtained from methyl
8-[4-(2-methoxyphenyl)-- 1-piperazinyl]-8-oxooctanoate (19e) by
Method Q, yield 34%. M.p. 135-137.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO), .delta.: 1.18-1.38 (m, 4H); 1.38-1.60 (m,
4H); 1.93 (t, 2H, J=7.3 Hz); 2.31 (t, 2H, J=7.2 Hz); 2.82-2.98 (m,
4H); 3.50-3.62 (m, 4H); 3.78 (s, 3H); 6.84-7.02 (m, 4H); 8.66 (s,
1H); 10.33 (s, 1H). HPLC analysis on Symmetry C.sub.8 column:
impurities<1.0% (column size 3.9.times.150 mm; mobile phase
acetonitrile-0.1M phosphate buffer (pH 2.5), 30:70; detector UV 220
nm; sample concentration 0.5 mg/ml; flow rate 1.1 mL/min). Anal.
Calcd for C.sub.19H.sub.29N.sub.3O.sub.4, %: C, 62.79; H, 8.04; N,
11.56. Found, %: C 62.71, H 8.07, N 11.64.
[1078] Method R--General Synthesis of Hydroxamic Acids from
Amidoesters
[1079] To a solution of amidoester 19f-w (1 mmol) in methanol (3-5
mL), a solution of hydroxylamine hydrochloride (0.278 g, 4 mmol) in
methanol (3 mL) followed by a solution of NaOH (0.320 g, 8 mmol) in
water (1 mL) were added. After stirring for 15-45 minutes at
ambient temperature, the reaction mixture was diluted with brine
and extracted with ethyl acetate (3.times.30 mL). The organic phase
was washed with brine, evaporated under reduced pressure by adding
benzene to remove traces of water several times, and dried in
vacuum. The crude product was crystallized or chromatographed on
silica gel to give the corresponding hydroxamic acid.
EXAMPLE 145
8-[4(2-Chloro-phenyl)-piperazin-1-yl]-8-oxo Octanoic Acid
Hydroxyamide (PX118791)
[1080] The title compound was obtained from methyl ethyl
8-[4-(2-chlorophenyl)-1-piperazinyl]-8-oxooctanoate (19f) using
Method R. The crude product was crystallized from acetonitrile,
yield 65%. M.p. 131-132.degree. C. .sup.1H NMR (DMSO-d.sub.6,
HMDSO), .delta.: 1.18-1.37(m, 4H); 1.40-1.60(m, 4H); 1.93(t, J=7.0
Hz, 2H); 2.33(t, J=7.3 Hz, 2H); 2.83-3.20(m, 4H); 3.53-3.66(m, 4H);
7.06(dt, J=1.6 and 7.8 Hz, 1H); 7.15(dd, J=1.4 and 8.2 Hz, 1H);
7.30(dt, J=1.4 and 8.2 Hz, 1H); 7.43(dd, J=1.6 and 7.8 Hz, 1H);
8.66(s, 1H); 10.33(s, 1H). HPLC analysis on Omnispher 5 C.sub.18
column: impurities<1% (column size 4.6.times.150 mm; mobile
phase 45% acetonitrile+55% 0.1M phosphate buffer (pH 2.5); detector
UV 254 nm; sample concentration 1.0 mg/ml; flow rate 1.0 mL/min).
Anal. Calcd for C.sub.18H.sub.26ClN.sub.3O.sub.3*0.4H.sub.2O- , %:
C, 57.64; H, 7.20; N, 11.20. Found, %: C, 57.72; H, 7.03; N,
11.24.
EXAMPLE 146
8-[4-(3-Chloro-phenyl)-piperazin-1-yl]-8-oxo Octanoic Acid
Hydroxyamide (PX118792)
[1081] The title compound was obtained from ethyl
8-[4-(3-chlorophenyl)-1-- piperazinyl]-8-oxooctanoate (19g) using
Method R. The crude product was crystallized from acetonitrile,
yield 56%. M.p. 122-124.degree. C. .sup.1H NMR (DMSO-d.sub.6,
HMDSO), .delta.: 1.19-1.38(m, 4H); 1.40-1.61(m, 4H); 1.93(t, J=7.2
Hz, 2H); 2.29(t, J=7.4 Hz, 2H); 2.80-3.20(m, 4H); 3.55-3.66(m, 4H);
6.81(d, J=7.8 Hz, 1H); 6.87-6.99(m, 2H); 7.22(t, J=7.8 Hz, 1H);
8.65(d, J=1.4 Hz, 1H); 10.33(s, 1H). HPLC analysis on Zorbax SB
C.sub.18 column: impurities .about.2.5% (column size 4.6.times.150
mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5),
gradient from 30:70 to 100:0; detector UV 254 nm; sample
concentration 1.0 mg/ml; flow rate 1.5 mL/min). Anal. Calcd for
C.sub.18H.sub.26ClN.sub.3O.sub.3%: C, 58.77; H, 7.12; N, 11.42.
Found, %: C, 58.41; H, 7.07; N, 11.44.
EXAMPLE 147
7-[4-(2-Chloro-phenyl)-piperazin-1-yl]-7-oxo Heptanoic Acid
Hydroxyamide (PX118793)
[1082] The title compound was obtained from ethyl
7-[4-(2-chlorophenyl)-1-- piperazinyl]-7-oxoheptanoate (19h) using
Method R. The crude product was crystallized from acetonitrile,
yield 62%. M.p. 128-130.degree. C. .sup.1H NMR (DMSO-d.sub.6,
HMDSO), .delta.: 1.17-1.36(m, 2H); 1.41-1.62(m, 4H); 1.94(t, J=7.0
Hz, 2H); 2.33(t, J=7.3 Hz, 2H); 2.80-3.20(m, 4H); 3.54-3.67(m, 4H);
7.06(dt, J=1.6 and 7.8 Hz, 1H); 7.15(dd, J=1.8 and 8.0 Hz, 1H);
7.30(dt, J=1.8 and 8.0 Hz, 1H); 7.43(dd, J=1.6 and 7.8 Hz, 1H);
8.67(d, J=1.8 Hz, 1H); 10.33(s, 1H). HPLC analysis on Omnispher 5
C.sub.18 column: impurities .about.1.8% (column size 4.6.times.150
mm; mobile phase 40% acetonitrile+60% 0.1M phosphate buffer (pH
2.5); detector UV 220 nm; sample concentration 1.0 mg/ml; flow rate
1.5 mL/min). Anal. Calcd for C.sub.17H.sub.24ClN.sub.3O.sub.3, %:
C, 57.70; H, 6.84; N, 11.88. Found, %: C, 57.76; H, 6.87; N,
11.79.
EXAMPLE 148
7-[4-(3-Chloro-phenyl)-piperazin-1-yl]-7-oxo Heptanoic Acid
Hydroxyamide (PX118794)
[1083] The title compound was obtained from ethyl
7-[4-(3-chlorophenyl)-1-- piperazinyl]-7-oxoheptanoate (19i) using
Method R. The crude product was crystallized from acetonitrile,
yield 48%. M.p. 120-122.degree. C. .sup.1H NMR (DMSO-d.sub.6,
HMDSO), .delta.: 1.17-1.34(m, 2H); 1.40-1.59(m, 4H); 1.93(t, J=7.3
Hz, 2H); 2.32(t, J=7.3 Hz, 2H); 3.07-3.24(m, 4H); 3.47-3.67(m, 4H);
6.80(dd, J=1.5 and 8.0 Hz, 1H); 6.86-6.98(m, 2H); 7.22(t, J=7.8 Hz,
1H); 8.65(d, J=1.8 Hz, 1H); 10.33(s, 1H). HPLC analysis on Zorbax
SB C.sub.18 column: impurities .about.3% (column size 4.6.times.150
mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5),
gradient from 30:70 to 100:0; detector UV 254 nm; sample
concentration 0.5 mg/ml; flow rate 1.5 mL/min). Anal. Calcd for
C.sub.17H.sub.24ClN.sub.3O.sub.3, %: C 57.70, H 6.84, N 11.88.
Found, %: C, 57.74; H, 6.86; N, 11.79.
EXAMPLE 149
8-[4-(Naphthalene-2-carbonyl)-piperazin-1-yl]-8-oxo Octanoic Acid
Hydroxyamide (PX118830)
[1084] The title compound was obtained from ethyl
8-[4-(2-naphthoyl)-1-pip- erazinyl]-8-oxooctanoate (19j) using
Method R. The crude product was crystallized from acetonitrile,
yield 54%. M.p. 133.5-134.5.degree. C. .sup.1H NMR (DMSO-d.sub.6,
HMDSO), .delta.: 1.20-1.60(m, 8H); 1.92(t, J=7.2 Hz, 2H);
2.20-2.40(m, 2H); 3.28-3.76(m, 8H); 7.50-7.66(m, 3H); 7.94-8.10(m,
4H); 8.66(d, J=1.6 Hz, 1H); 10.32(s, 1H). HPLC analysis on Alltima
C.sub.18 column: impurities 3% (column size 4.6.times.150 mm;
mobile phase 40% acetonitrile+60% 0.1M phosphate buffer (pH 2.5);
detector UV 220 nm; sample concentration 0.5 mg/ml; flow rate 1.3
mL/min). Anal. Calcd for C.sub.23H.sub.29N.sub.3O.sub.4, %: C,
67.13; H, 7.10; N, 10.21. Found, %: C 66.90, H 7.09, N 10.23.
EXAMPLE 150
8-(4-Benzoyl-piperazin-1-yl)-8-oxo Octanoic Acid Hydroxyamide
(PX118831)
[1085] The title compound was obtained from ethyl
8-(4-benzoyl-1-piperazin- yl)-8-oxooctanoate (19k) using Method R.
The crude product was crystallized from acetonitrile, yield 29%.
M.p. 100-101.degree. C. .sup.1H NMR (DMSO-d.sub.6, HMDSO), .delta.:
1.18-1.36(m, 4H); 1.38-1.58(m, 4H); 1.92(t, J=7.4 Hz, 2H); 2.30(t,
J=6.6 Hz, 2H); 3.49(m, 8H); 7.38-7.50(m, 5H); 8.66(s, 1H); 10.32(s,
1H). HPLC analysis on Alltima C.sub.18 column: impurities 2.5%
(column size 4.6.times.150 mm; mobile phase 20% acetonitrile+80%
0.1M phosphate buffer (pH 2.5); detector UV 254 nm; sample
concentration 1.0 mg/ml; flow rate 1.7 mL/min). Anal. Calcd for
C.sub.19H.sub.27N.sub.3O.sub.4*0.35H.sub.2O, %: C, 62.06; H, 7.59;
N, 11.43. Found, %: C 62.03, H 7.50, N 11.33.
EXAMPLE 151
8-[4-(4-Dimethylamino-benzoyl-piperazin-1-yl]-8-oxo Octanoic Acid
Hydroxyamide (PX118832)
[1086] The title compound was obtained from ethyl
8-{4-[4-(dimethylamino)b- enzoyl]-1-piperazinyl}-8-oxooctanoate
(19l) using Method R. The crude product was crystallized from
acetonitrile, yield 74%. M.p. 90-92.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO), .delta.: 1.18-1.30(m, 4H); 1.40-1.60(m, 4H);
1.93(t, J=7.2 Hz, 2H); 2.30(t, J=7.0 Hz, 2H); 2.95(s, 6H);
3.44-3.52(m, 8H); 6.70(d, J=8.6 Hz, 2H); 7.29(d, J=8.6 Hz, 2H);
8.64(s, 1H); 10.32(s, 1H). HPLC analysis on Zorbax SB C.sub.18
column: impurities .about.10% (column size 4.6.times.150 mm; mobile
phase gradient 15 min 10% acetonitrile/90% 0.1M phosphate buffer
(pH 2.5)-100% 0.1M phosphate buffer; detector UV 254 nm; sample
concentration 0.5 mg/ml; flow rate 1.0 mL/min). Anal. Calcd for
C.sub.21H.sub.32N.sub.4O.su- b.4*0.5H.sub.2O, %: C, 61.00; H, 8.04;
N, 13.55. Found, %: C, 60.98; H, 7.85; N, 13.37.
EXAMPLE 152
8-(4(4-Methoxyphenyl)-piperazin-1-yl]-8-oxo Octanoic Acid
Hydroxyamide (PX118846)
[1087] The title compound was obtained from ethyl
8-[4-(4-methoxyphenyl)-1- -piperazinyl]-8-oxooctanoate (19m) using
Method R. The crude product was crystallized from acetonitrile,
yield 48%. M.p. 149-150.degree. C. .sup.1H NMR (DMSO-d.sub.8,
HMDSO), .delta.: 1.18-1.33(m, 4H); 1.39-1.58(m, 4H); 1.93(t, J=7.2
Hz, 2H); 2.32(t, J=7.4 Hz, 2H); 2.88-3.03(m, 4H); 3.52-3.61(m, 4H);
3.68(s, 3H); 6.83(dt, J=9.6 and 2.8 Hz, 2H); 6.90(dt, J=9.6 and 2.8
Hz, 2H); 8.64(s, 1H); 10.32(s, 1H). HPLC analysis on Alltima
C.sub.18 column: impurities 1.5% (column size 4.6.times.150 mm;
mobile phase 25% acetonitrile+75% 0.1M phosphate buffer (pH 2.5);
detector UV 220 nm; sample concentration 0.5 mg/ml; flow rate 1.5
mL/min). Anal. Calcd for C.sub.19H.sub.29N.sub.3O.sub.4, %: C,
62.79; H, 8.04; N, 11.56. Found, %: C 62.65, H 8.09, N 11.53.
EXAMPLE 153
8-[4(3-Methoxyphenyl)-piperazin-1-yl]-8-oxo Octanoic Acid
Hydroxyamide (PX118847)
[1088] The title compound was obtained from ethyl
8-[4-(3-methoxyphenyl)-1- -piperazinyl]-8-oxooctanoate (19n) using
Method R. The crude product was crystallized from acetonitrile,
yield 69%. M.p. 122-122.5.degree. C. .sup.1H NMR (DMSO-d.sub.6,
HMDSO), .delta.: 1.18-1.36(m, 4H); 1.39-1.58(m, 4H); 1.93(t, J=7.0
Hz, 2H); 2.32(t, J=7.6 Hz, 2H); 3.03-3.17(m, 4H); 3.50-3.63(m, 4H);
3.71(s, 3H); 6.39(dd, J=8.0 and 2.0 Hz, 1H); 6.46(t, J=2.0 Hz, 1H);
6.52(dd, J=8.0 and 2.0 Hz, 1H); 7.12(t, J=8.0 Hz, 1H); 8.63(d,
J=1.6 Hz, 1H); 10.31(s, 1H). HPLC analysis on Alltima C.sub.18
column: impurities 1% (column size 4.6.times.150 mm; mobile phase
25% acetonitrile+75% 0.1M phosphate buffer (pH 2.5); detector UV
220 nm; sample concentration 0.5 mg/ml; flow rate 1.5 mL/min).
Anal. Calcd for C.sub.19H.sub.29N.sub.3O.sub.4, %: C 62.79, H 8.04,
N 11.56. Found, %: C, 62.65; H, 8.06; N, 11.43.
EXAMPLE 154
N-Hydroxy-8-[4-(4-nitrophenyl)-1-piperazinyl]-8-oxooctanamide
(PX118849)
[1089] The title compound was obtained from ethyl
8-[4-(4-nitrophenyl)-1-p- iperazinyl]-8-oxooctanoate (19o) using
Method R. The crude product was crystallized from acetonitrile,
yield 31%. M.p. 125-127.degree. C. .sup.1H NMR (DMSO-d.sub.6,
HMDSO), .delta.: 1.20-1.28 (m, 4H); 1.33-1.50(m, 4H); 1.93(t, J=7.6
Hz, 2H); 2.33(t, J=7.2 Hz, 2H); 3.40-3.70(m, 8H); 7.00(d, J=9.0 Hz,
2H); 8.07(d, J=9.0 Hz, 2H); 8.67(s, 1H); 10.33(s, 1H). HPLC
analysis on Alltima C.sub.18 column: impurities 2.5% (column size
4.6.times.150 mm; mobile phase 40% acetonitrile+60% 0.1M phosphate
buffer (pH 2.5); detector UW 215 nm; sample concentration 0.5
mg/ml; flow rate 1.5 mL/min). Anal. Calcd for
C.sub.18H.sub.26N.sub.4- O.sub.5, %: C, 57.13; H, 6.93; N, 14.80.
Found, %: C, 57.06; H, 6.94; N, 14.72.
EXAMPLE 155
N-Hydroxy-8-{4-[2-(5-methoxy-1H-indol-3-yl)acetyl]-1-piperazinyl}-8-oxooct-
anamide (PX118927)
[1090] The title compound was obtained from methyl
8-{4-[2-(5-methoxy-1H-i-
ndol-3-yl)acetyl]-1-piperazinyl}-8-oxooctanoate (19M using Method
R. The crude product was chromatographed on reverse phase Silasorb
CL 18 with methanol -0.1% H.sub.3PO.sub.4 as eluent. The eluate was
evaporated, the residue was dissolved in ethyl acetate, the extract
was washed with water, evaporated, and dried. Yield 35%. Foam.
.sup.1H NMR (DMSO-d.sub.6, HMDSO), .delta.: 1.13-1.32(m, 4H);
1.34-1.55(m, 4H); 1.91(t, J=7.3 Hz, 2H); 2.17-2.31(m, 2H);
3.24-3.57(m, 8H, overlapped with a signal of water); 3.73(s, 3H);
3.75(s, 2H); 6.71 (dd, J=8.8 and 2.4 Hz, 1H); 7.05(d, J=2.4 Hz,
1H); 7.16(br s, 1H); 7.22(d, J=8.8 Hz, 1H); 8.67(s, 1H); 10.33(s,
1H); 10.75(s, 1H). HPLC analysis on Kromasil C.sub.18 column:
impurities 5% (column size 4.6.times.150 mm; mobile phase 20%
acetonitrile+80% 0.2M acetate buffer (pH 5.0); detector UV 230 nm;
sample concentration 1.0 mg/ml; flow rate 1.5 mL/min). Anal. Calcd
for C.sub.23H.sub.32N.sub.4O.sub.5*0.25H.sub.2O, containing 4% of
inorganic impurities, %: C, 59.06; H, 7.00; N, 11.98. Found, %: C,
59.01; H, 7.02; N, 11.97.
EXAMPLE 156
N-Hydroxy-8-{4-[2-(2-naphthyloxy)ethyl]-1-piperazinyl}-8-oxooctanamide
(PX118930)
[1091] The title compound was obtained from methyl
8-{4-[2-(2-naphthyloxy)- ethyl]-1-piperazinyl}-8-oxooctanoate (19r)
using Method R. The crude product was precipitated from diethyl
ether, yield 35%. Foam. .sup.1H NMR (DMSO-d.sub.6, HMDSO), .delta.:
1.16-1.31(m, 4H); 1.37-1.54(m, 4H); 1.93(t, J=7.2 Hz, 2H); 2.27(t,
J=7.4 Hz, 2H); 2.41-2.55(m, 4H, overlapped with a signal of DMSO);
2.79(t, J=5.9 Hz, 2H); 3.39-3.49(m, 4H); 4.21(t, J=5.9 Hz, 2H);
7.16(dd, J=8.8 and 2.4 Hz, 1H); 7.29-7.50(m, 3H); 7.76-7.86(m, 3H);
8.67(s, 1H); 10.33(s, 1H). HPLC analysis on Alltima C.sub.18
column: impurities 1% (column size 4.6.times.150 mm; mobile phase
25% acetonitrile+75% 0.1M phosphate buffer (pH 2.5); detector UV
220 nm; sample concentration 1.0 mg/ml; flow rate 1.3 mL/min).
Anal. Calcd for C.sub.24H.sub.33N.sub.3O.sub.4*1.25H.sub.2O, %: C,
64.05; H, 7.95; N, 9.34. Found, %: C, 64.17; H, 7.91; N, 9.28.
EXAMPLE 157
N-Hydroxy-8-{4-[2-(1-naphthyloxy)acetyl]-1-piperazinyl}-8-oxooctanamide
(PX118931)
[1092] The title compound was obtained from ethyl
8-{4-[2-(1-naphthyloxy)a- cetyl]-1-piperazinyl}-8-oxooctanoate
(19s) using Method R. The crude product was precipitated from
diethyl ether, yield 34%. Foam. .sup.1H NMR (DMSO-d.sub.6, HMDSO),
.delta.: 1.14-1.33(m, 4H); 1.37-1.56(m, 4H); 1.92(t, J=7.0 Hz, 2H);
2.21-2.36(m, 2H); 3.22-3.61(m, 8H, overlapped with a signal of
H.sub.2O); 3.92(s, 2H); 7.34-7.57(m, 3H); 7.80-7.95(m, 4H); 8.66(s,
1H); 10.32(s, 1H). HPLC analysis on Alltima C.sub.18 column:
impurities 1% (column size 4.6.times.150 mm; mobile phase 50%
acetonitrile+50% 0.1M phosphate buffer (pH 2.5); detector UV 220
nm; sample concentration 1.0 mg/ml; flow rate 1.0 mL/min). Anal.
Calcd for C.sub.24H.sub.31N.sub.3O.sub.5, %: C 65.29, H 7.08, N
9.52. Found, %: C, 65.15; H, 7.45; N, 9.40.
EXAMPLE 158
N-Hydroxy-8-{4-[2-(5-methoxy-1H-indol-3-yl)ethyl]-1-piperazinyl}-8-oxoocta-
namide Oxalate (PX118932)
[1093] The title compound was obtained from methyl
8-{4-[2-(5-methoxy-1H-i-
ndol-3-yl)ethyl]-1-piperazinyl}-8-oxooctanoate (19t) using Method
R. The crude product (ca. 0.33 mmol) was dissolved in abs. ethanol
(1.5 mL) and a solution of oxalic acid dihydrate (0.1 g, 0.79 mmol)
in abs. ethanol (1 mL) was added. The reaction mixture was stirred
for 2 hours at ambient temperature, the precipitate was filtered
and washed with diethyl ether. The product was crystallized from
ethanol and dried, yield 70%. M.p. 122-125.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO), .delta.: 1.17-1.35(m, 4H); 1.39-1.57(m, 4H);
1.93(t, J=7.6 Hz, 2H); 2.32(t, J=7.4 Hz, 2H); 2.93-3.17(m, 8H);
3.56-3.72(m, 4H); 3.77(s, 3H); 6.73(dd, J=8.8 and 2.2 Hz, 1H);
7.03(d, J=2.2 Hz, 1H); 7.16(d, J=2.2 Hz, 1H); 7.23(d, J=8.8 Hz,
2H); 10.35(s, 1H); 10.75(s, 1H). HPLC analysis on Zorbax SB
C.sub.18 column: impurities .about.7% (column size 4.6.times.150
mm; mobile phase 15 min gradient: acetonitrile-0.1M phosphate
buffer (pH 2.5); 30/70-100/0; detector UV 220 nm; sample
concentration 0.5 mg/ml; flow rate 1.5 mL/min). Anal. Calcd for
C.sub.23H.sub.34N.sub.4O.sub.4*1.3 (COOH).sub.2, %: C, 56.15; H,
6.74; N, 10.23. Found, %: C, 56.00; H, 6.86; N, 10.12.
EXAMPLE 159
8-{4-[2-(1-Benzothiophen-3-yl)acetyl]-1-piperazinyl}-N-hydroxy-8-oxooctana-
mide (PX118967)
[1094] The title compound was obtained from ethyl
8-{4-[2-(1-benzothiophen-
-3-yl)acetyl]-1-piperazinyl}-8-oxooctanoate (19u) using Method R.
The crude product was crystallized from acetonitrile, yield 35%.
M.p. 140-141.degree. C. .sup.1H NMR (DMSO-d.sub.6, HMDSO), .delta.:
1.15-1.34(m, 4H); 1.37-1.56(m, 4H); 1.92(t, J=7.3 Hz, 2H); 2.29(t,
J=7.3 Hz, 2H); 3.36-3.60(m, 8H); 3.98(s, 2H); 7.34-7.44(m, 2H);
7.51(s, 1H); 7.78-7.85(m, 1H); 7.93-8.05(m, 1H); 8.65(s, 1H);
10.32(s, 1H). HPLC analysis on Omnispher 5 C.sub.18 column:
impurities 1% (column size 4.6.times.150 mm; mobile phase 50%
acetonitrile+50% 0.1M phosphate buffer (pH 2.5); detector UV 215
nm; sample concentration 0.5 mg/ml; flow rate 1.3 mL/min). Anal.
Calcd for C.sub.22H.sub.29N.sub.3O.sub.4S, %: C 61.23; H, 6.77; N,
9.74. Found, %: C 60.76, H 6.71, N 9.82.
EXAMPLE 160
7-[4-(3,4-Dichlorophenyl)-1-piperazinyl]-N-hydroxy-7-oxoheptanamide
(PX118989)
[1095] The title compound was obtained from ethyl
7-[4-(3,4-dichlorophenyl- )-1-piperazinyl]-7-oxoheptanoate (19)
using Method R. The crude product was crystallized from ethyl
acetate-methanol (9:1), yield 43%. M.p. 125-126.degree. C. .sup.1H
NMR (DMSO-d.sub.6, HMDSO), .delta.: 1.14-1.34(m, 2H); 1.38-1.59(m,
4H); 1.93(t, J=7.3 Hz, 2H); 2.32(t, J=7.0 Hz, 2H); 3.07-3.26(m,
4H); 3.48-3.63(m, 4H); 6.94(dd, J=8.8 and 2.9 Hz, 1H); 7.14(d,
J=2.9 Hz, 1H); 7.40(d, J=8.8 Hz, 1H); 8.67(d, J=1.5 Hz, 1H);
10.33(s, 1H). HPLC analysis on Omnispher 5 C.sub.18 column:
impurities 1% (column size 4.6.times.150 mm; mobile phase 40%
acetonitrile+60% 0.1M phosphate buffer (pH 2.5); detector UV 215
nm; sample concentration 1.0 mg/ml; flow rate 1.3 mL/min). Anal.
Calcd for C.sub.17H.sub.23Cl.sub.2N.s- ub.3O.sub.3, %: C, 52.59; H,
5.97; N, 10.82. Found, %: C, 52.50; H, 5.90; N, 10.75.
EXAMPLE 161
7-[4-(4-Fluorophenyl)-1-piperazinyl]-N-hydroxy-7-oxoheptanamide
(PX118990)
[1096] The title compound was obtained from ethyl
7-[4-(4-fluorophenyl)-1-- piperazinyl]-7-oxoheptanoate (19v) using
Method R The crude product was crystallized from ethyl
acetate-methanol (9:1), yield 29%. M.p. 119-120.degree. C. .sup.1H
NMR (DMSO-d.sub.6, HMDSO), .delta.: 1.18-1.34(m, 2H); 1.39-1.59(m,
4H); 1.93(t, J=7.3 Hz, 2H); 2.32(t, J=7.3H 2H); 2.94-3.11(m, 4H);
3.51-3.62(m, 4H); 6.92-7.13(m, 4H); 8.67(s, 1H); 10.33(s, 1H). HPLC
analysis on Alltima C.sub.18 column: impurities 2% (column size
4.6.times.150 mm; mobile phase 35% acetonitrile+65% 0.1M phosphate
buffer (pH 2.5); detector UV 254 nm; sample concentration 1.0
mg/ml; flow rate 1.0 mL/min). Anal. Calcd for
C.sub.17H.sub.24FN.sub.3O.s- ub.3, %: C, 60.52; H, 7.17; N, 12.45.
Found, %: C, 60.42; H, 7.22; N, 12.32.
EXAMPLE 162
7-[4-(4-Chlorophenyl)-1-piperazinyl]-N-hydroxy-7-oxoheptanamide
(PX118991)
[1097] The title compound was obtained from ethyl
7-[4-(4-chlorophenyl)-1-- piperazinyl]-7-oxoheptanoate (19w) using
Method R. The crude product was crystallized from ethyl
acetate-methanol (9:1), yield 21%. M.p. 119-121.degree. C. .sup.1H
NMR (DMSO-d.sub.6, HMDSO), .delta.: 1.19-1.34(m, 2H); 1.39-1.59(m,
4H); 1.93(t, J=7.3 Hz, 2H); 2.33(t, J=7.3 Hz, 2H); 3.01-3.18(m,
4H); 3.50-3.64(m, 4H); 6.95(d, J=8.8 Hz, 2H); 7.24(d, J=8.8 Hz,
2H); 8.67(s, 1H); 10.33(s, 1H). HPLC analysis on Omnispher 5
C.sub.18 column: impurities 2.2% (column size 4.6.times.150 mm;
mobile phase 35% acetonitrile+65% 0.1M phosphate buffer (pH 2.5);
detector UV 215 nm; sample concentration 1.0 mg/ml; flow rate 1.3
mL/min). Anal. Calcd for C.sub.17H.sub.24ClN.sub.3O.sub.3, %: C,
57.70; H, 6.84; N, 11.88. Found, %: C, 57.75; H, 6.84; N,
11.80.
[1098] Method S--General Synthesis of Hydroxamic Acids from
O-benzyl Hydroxamates
[1099] To a solution of O-benzylhydroxamate 22a-k (1 mmol) in
methanol (5-10 mL), 5% palladium on activated carbon catalyst
(0.050 g) was added and the black suspension was vigorously stirred
under hydrogen atmosphere until initbal compound disappeared. The
reaction mixture was filtered through a small amount of silica gel
(ca. 1-2 cm thin layer), the sorbent was washed with methanol, and
the filtrate was evaporated in vacuum. The crude product was
crystallized or chromatographed on silica gel to give the
corresponding hydroxamic acid.
EXAMPLE 163
8-[4-(4-Cyanobenzoyl)-piperazin-1-yl]-8-oxo Octanoic Acid
Hydroxyamide (PX118844)
[1100] The title compound was obtained from
N-(benzyloxy)-8-[4-(4-cyanoben-
zoyl)-1-piperazinyl]-8-oxooctanamide (22a), using Method S, yield
74%. M.p. 150-150.5.degree. C. .sup.1H NMR (DMSO-d.sub.6, HMDSO),
.delta.: 1.18-1.38(m, 4H); 1.40-1.60(m, 4H); 1.92(t, J=7.0 Hz, 2H);
2.22-2.40(m, 2H); 3.20-3.70(m, overlapped with a signal of
H.sub.2O); 7.61 (d, J=8.0 Hz, 2H); 7.94(d, J=8.0 Hz, 2H); 8.64(s,
1H); 10.32(s, 1H). HPLC analysis on Omnispher 5 C.sub.18 column:
impurities 2% (column size 4.6.times.150 mm; mobile phase 20%
acetonitrile+80% 0.1M phosphate buffer (pH 2.5); detector UV 254
nm; sample concentration 0.5 mg/ml; flow rate 1.0 mL/min). Anal.
Calcd for C.sub.20H.sub.26N.sub.4O.sub.4*0.5H.sub.2O, %: C, 60.74;
H, 6.88; N, 14.17. Found, %: C, 60.83; H, 6.82; N, 13.88.
EXAMPLE 164
7-Oxo-7-(4-pyridin-2-yl-piperazin-1-yl]-heptanoic Acid Hydroxyamide
Oxalate (PX118845)
[1101] The title compound was obtained from
N-(benzyloxy)-7-oxo-7-[4-(2-py- ridinyl)-1-piperazinyl]heptanamide
(22b), using Method S. The crude product (ca. 0.33 mmol) was
dissolved in abs. ethanol (1.5 mL) and a solution of oxalic acid
dihydrate (0.1 g, 0.79 mmol) in abs. ethanol (1 mL) was added. The
reaction mixture was stirred for 2 hours at ambient temperature,
the precipitate was filtered and washed with diethyl ether. The
product was crystallized from ethanol and dried, yield 65%. M.p.
118-122.degree. C. .sup.1H NMR (DMSO-d.sub.6, HMDSO), .delta.:
1.20-1.40(m, 2H); 1.42-1.65(m, 4H); 2.35(t, J=7.2 Hz, 2H); 2.77(t,
J=7.2 Hz, 2H); 3.37-3.63(m, 8H); 6.65(dd, J=7.2 and 5.0 Hz, 1H);
6.83(d, J=8.2 Hz, 1H); 7.55(ddd, J=8.2, 7.2 and 1.8 Hz, 1H);
8.11(dd, J=5.0 and 1.8 Hz, 1H). HPLC analysis on Ultra Aqueous
C.sub.18 column: impurities 2.3% (column size 4.6.times.150 mm;
mobile phase 5% acetonitrile+95% 0.1M phosphate buffer (pH 2.5);
detector UV 215 nm; sample concentration 0.5 mg/mL; flow rate 1.5
mL/min). Anal. Calcd for C.sub.16H.sub.24N.sub.4O.su- b.3*0.5
C.sub.2H.sub.2O.sub.4*0.5H.sub.2O, %: C, 54.53; H, 7.00; N, 14.96.
Found, %: C, 54.43; H, 7.20; N, 14.84.
EXAMPLE 165
8-(4-{2-[4-(Dimethylamino)phenyl]acetyl}-1-piperazinyl)-N-hydroxy-8-oxooct-
anamide (PX118848)
[1102] The title compound was obtained from
N-(benzyloxy)-8-(4-{2-[4-(dime-
thylamino)phenyl]acetyl}-1-piperazinyl)-8-oxooctanamide (22c),
using Method S. The crude product was precipitated from diethyl
ether, yield 63%. M.p. 77-79.degree. C. .sup.1H NMR (DMSO-d.sub.8,
HMDSO), .delta.: 1.18-1.34(m, 4H); 1.36-1.56(m, 4H); 1.92(t, J=7.2
Hz, 2H); 2.27(t, J=7.2 Hz, 2H); 2.85(s 6H); 3.25-3.50(m, 8H,
overlapped with a signal of H.sub.2O); 3.58(s, 2H); 6.66(d, J=8.2,
2H); 7.03(d, J=8.2 Hz, 2H); 8.65(s, 1H); 10.32(s, 1H). HPLC
analysis on Alltima C.sub.18 column: impurities 4% (column size
4.6.times.150 mm; mobile phase 15% acetonitrile+85% 0.1M phosphate
buffer (pH 2.5); detector UV 215 nm; sample concentration 0.5
mg/ml; flow rate 1.5 mL/min). Anal. Calcd for
C.sub.22H.sub.34N.sub.4O.sub.4*0.5H.sub.2O, %: C, 61.80; H, 8.25;
N, 13.10. Found, %: C, 61.90; H, 8.18; N, 13.11.
EXAMPLE 166
N-Hydroxy-8-oxo-8-[4-(2-pyrimidinyl)-1-piperazinyl]octanamide
(PX118850)
[1103] The title compound was obtained from
N-(benzyloxy)-8-oxo-8-[4(2-pyr- imidinyl)-1-piperazinyl]octanamide
(22d), using Method S. The crude product was crystallized from
methanol, yield 37%. M.p. 132-133.5.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO), .delta.: 1.18-1.36(m, 4H); 1.38-1.59(m, 4H);
1.93(t, J=7.3 Hz, 2H); 2.33(t, J=7.3 Hz, 2H); 3.46-3.58(m, 4H);
3.62-3.80(m, 4H); 6.65(t, J=4.8 Hz, 1H); 8.37(d, J=4.8 Hz, 2H);
8.65(br s, 1H); 10.29(br s, 1H). HPLC analysis on Alltima C.sub.18
column: impurities 1% (column size 4.6.times.150 mm; mobile phase
20% acetonitrile+80% 0.1M phosphate buffer (pH 2.5); detector UV
230 nm; sample concentration 0.5 mg/ml; flow rate 1.5 mL/min).
Anal. Calcd for C.sub.16H.sub.25N.sub.5O.sub.3, %: C, 57.30; H,
7.51; N, 20.88. Found, %: C, 57.23; H, 7.58; N, 20.80.
EXAMPLE 167
8-{4-[4-(Dimethylamino)phenethyl]-1-piperazinyl}N-hydroxy-8-oxooctanamide
(PX118928)
[1104] The title compound was obtained from
N-(benzyloxy)-8-(4-{3-[3-(dime-
thylamino)phenyl]propyl}-1-piperazinyl)-8-oxooctanamide (22e),
using Method S. The crude product was crystallized from
acetonitrile, yield 45%. M.p. 103-105.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO), .delta.: 1.11-1.33(m, 4H); 1.35-1.54(m, 4H);
1.92(t, J=7.2 Hz, 2H); 2.26(t, J=7.4 Hz, 2H); 2.24-2.66(m, 8H,
partially overlapped with a signal of DMSO); 2.83(s, 6H);
3.25-3.50(m, 4H, partially overlapped with a signal of water);
6.64(d, J=8.6 Hz, 2H); 7.00(d, J=8.6 Hz, 2H); 8.67(s, 1H); 10.33(s,
1H). HPLC analysis on Alltima C.sub.18 column: impurities 1%
(column size 4.6.times.150 mm; mobile phase 8% acetonitrile+92%
0.1M phosphate buffer (pH 2.5); detector UV 215 nm; sample
concentration 1.0 mg/ml; flow rate 1.3 mL/min). Anal. Calcd for
C.sub.22H.sub.38N.sub.4O.su- b.3, containing 1% of inorganic
impurities, %: C 64.66, H 8.88, N 13.71. Found, %: C, 64.64; H,
8.94; N, 13.70.
EXAMPLE 168
N-Hydroxy-8-{4-[2-(2-naphthyloxy)acetyl]-1-piperazinyl}-8-oxooctanamide
(PX118929)
[1105] The title compound was obtained from
N-(benzyloxy)-8-{4-[2-(2-napht-
hyloxy)acetyl]-1-piperazinyl}-8-oxooctanamide (22f), using Method
S. The crude product was crystallized from acetonitrile, yield 45%.
M.p. 139-140.5.degree. C. .sup.1H NMR (DMSO-d.sub.6, HMDSO),
.delta.: 1.17-1.35(m, 4H); 1.37-1.56(m, 4H); 1.93(t, J=7.2 Hz, 2H);
2.32(t, J=7.0 Hz, 2H); 3.39-3.60(m, 8H, overlapped with a signal of
H.sub.2O); 4.97(s, 2H); 7.17-7.51(m, 4H); 7.37-7.89(m, 3H); 8.67(s,
1H); 10.34(s, 1H). TLC: single spot at R.sub.f 0.3 (ethyl
acetate-methanol, 4:1; detection--UV-254 nm). Anal. Calcd for
C.sub.24H.sub.31N.sub.3O.sub.5, containing 1% of inorganic
impurities, %: C, 64.64; H, 7.01; N, 9.42. Found, %: C, 64.64; H,
6.96; N, 9.45.
EXAMPLE 169
N-Hydroxy-7-{4-[3-(1H-indol-3-yl)propanoyl]-1-piperazinyl}-7-oxoheptanamid-
e (PX118968)
[1106] The title compound was obtained from
N-(benzyloxy)-7-{4-[3-(1H-indo-
l-3-yl)propanoyl]-1-piperazinyl}-7-oxoheptanamide (22g), using
Method S. The crude product was crystallized from methanol-ethyl
acetate (1:2), yield 40%. M.p. 152.5-153.5.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO), .delta.: 1.13-1.33(m, 2H); 1.36-1.57(m, 4H);
1.92(t, J=7.0 Hz, 2H); 2.27(t, J=7.0 Hz, 2H); 2.67(t, J=7.3 Hz,
2H); 2.93(t, J=7.3 Hz, 2H); 3.25-3.52(m, 8H, overlapped with a
signal of H.sub.2O); 6.96(t, J=7.3 Hz, 1H); 7.05(t, J=7.3 Hz, 1H);
7.14(d, J=2.0 Hz, 1H); 7.33(d, J=7.3 Hz, 1H); 7.51(d, J=7.3 Hz,
1H); 8.67(s, 1H); 10.34(s, 1H); 10.78(s, 1H). HPLC analysis on
Alltima C.sub.18 column: impurities 1% (column size 4.6.times.150
mm; mobile phase 20% acetonitrile+80% 0.1M phosphate buffer (pH
2.5); detector UV 215 nm; sample concentration 0.25 mg/ml; flow
rate 1.5 mL/min). Anal. Calcd for
C.sub.22H.sub.30N.sub.4O.sub.4*0.5H.sub.2O*0- .1 EtOAc, %: C,
62.59; H, 7.42; N, 12.81. Found, %: C, 62.61; H, 7.35; N,
12.92.
EXAMPLE 170
N-Hydroxy-7-[4-(1H-indol-3-ylcarbonyl)-1-piperazinyl]-7-oxoheptanamide
(PX118969)
[1107] The title compound was obtained from
N-(benzyloxy)-7-[4-(1H-indol-3-
-ylcarbonyl)-1-piperazinyl]-7-oxoheptanamide (22h), using Method S.
The crude product was crystallized from methanol-ethyl acetate
(2:3), yield 52%. M.p. 86-88.degree. C. .sup.1H NMR (DMSO-d.sub.6,
HMDSO), .delta.: 1.16-1.35(m, 2H); 1.39-1.59(m, 4H); 1.93(t, J=7.3
Hz, 2H); 2.32(t, J=7.3 Hz, 2H); 3.43-3.70(m, 8H); 7.04-7.21 (m,
2H); 7.44(dd, J=7.3 and 1.5 Hz, 1H); 7.66-7.75(m, 2H); 8.67(s, 1H);
10.34(s, 1H); 11.62(s, 1H). HPLC analysis on Omnispher 5 C.sub.18
column: impurities 2% (column size 4.6.times.150 mm; mobile phase
20% acetonitrile+80% 0.1M phosphate buffer (pH 2.5); detector UV
215 nm; sample concentration 0.5 mg/ml; flow rate 1.3 mL/min).
Anal. Calcd for C.sub.20H.sub.26N.sub.4O.sub.4*0.5H.sub.2O*0- .2
CH.sub.2Cl.sub.2, containing 2% of inorganic impurities, %: C,
58.18; H, 6.56; N, 13.30. Found, %: C, 58.12; H, 6.54; N,
13.33.
EXAMPLE 171
N-Hydroxy-7-{4-[3-(1H-indol-3-yl)propyl]-1-piperazinyl}-7-oxoheptanamide
(PX118970)
[1108] The title compound was obtained from
N-(benzyloxy)-7-{4-[3-(1H-indo-
l-3-yl)propyl]-1-piperazinyl}-7-oxoheptanamide (22i), using Method
S. The crude product was crystallized from methanol-ethyl acetate
(2:3), yield 23%. M.p. 165-166.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO), .delta.: 1.11-1.32(m, 2H); 1.35-1.57(m, 4H);
1.79(t, J=7.3 Hz, 2H); 1.92(t, J=7.0 Hz, 2H); 2.18-2.41(m, 10H);
2.68(t, J=7.3 Hz, 2H); 3.42(br s, 4H); 6.90-7.06(m, 2H); 7.10(s,
1H); 7.31(d, J=7.3 Hz, 1H); 7.49(d, J=7.3 Hz, 1H); 8.66(s, 1H);
10.32(s, 1H); 10.74(s, 1H). HPLC analysis on .mu. Bondasphere
Phenyl column: impurities 2.5% (column size 4.6.times.150 mm;
mobile phase 20% acetonitrile+80% 0.1M phosphate buffer (pH 2.5);
detector UV 210 nm; sample concentration 0.5 mg/ml; flow rate 1.5
mL/min). Anal. Calcd for C.sub.22H.sub.32N.sub.4O.sub.3, %: C,
65.97; H, 8.05; N, 13.99. Found, %: C, 65.85; H, 8.10; N,
13.97.
EXAMPLE 172
N-Hydroxy-7-[4-(1H-indol-3-ylmethyl)-1-piperazinyl]-7-oxoheptanamide
(PX118978)
[1109] The title compound was obtained from
N-(benzyloxy)-7-[4-(1H-indol-3-
-ylmethyl)-1-piperazinyl]-7-oxoheptanamide (22j), using Method S.
The crude product was crystallized from methanol-ethyl acetate
(2:3), yield 52%. M.p. 65-67.degree. C. .sup.1H NMR (DMSO-d.sub.6,
HMDSO), .delta.: 1.10-1.30(m, 2H); 1.34-1.56(m, 4H); 1.91(t, J=7.3
Hz, 2H); 2.24(t, J=7.0 Hz, 2H); 2.23-2.50(m, 4H, overlapped with a
signal of DMSO); 3.25-3.48(m, 4H, overlapped with a signal of
water); 3.65(s, 2H); 6.97(t, J=7.3 Hz, 1H); 7.07(t, J=7.3 Hz, 1H);
7.23(s, 1H); 7.34(d, J=7.3 Hz, 1H); 7.63(d, J=7.3 Hz, 1H); 8.66(s,
1H); 10.32(s, 1H); 10.96(s, 1H). HPLC analysis on Omnispher
C.sub.18 column: impurities 2% (column size 4.6.times.150 mm;
mobile phase 15% acetonitrile+85% 0.1M phosphate buffer (pH 2.5);
detector UV 210 nm; sample concentration 0.5 mg/ml; flow rate 1.0
mL/min). Anal. Calcd for C.sub.20H.sub.28N.sub.4O.sub.3*
0.4H.sub.2O*0.25 EtOAc, containing 4% of inorganic material, %: C,
60.49; H, 7.86; N, 13.44. Found, %: C, 60.65; H, 7.43; N,
13.39.
EXAMPLE 173
7-[4-(3,4-Dimethylphenyl)-1-piperazinyl]-N-hydroxy-7-oxoheptanamide
(PX118994)
[1110] The title compound was obtained from
N-(benzyloxy)-7-[4(3,4-dimethy-
lphenyl)-1-piperazinyl]-7-oxoheptanamide (22k), using Method S. The
crude product was crystallized from acetonitrile, yield 73%. M.p.
119.5-120.5.degree. C. .sup.1H NMR (DMSO-d.sub.6, HMDSO), .delta.:
1.18-1.34(m, 2H); 1.39-1.59(m, 4H); 1.93(t, J=7.3 Hz, 2H); 2.11(s,
3H); 2.16(s, 3H); 2.32(t, J=7.3 Hz, 2H); 2.93-3.09(m, 4H);
3.49-3.61(m, 4H); 6.66(dd, J=8.8 and 2.2 Hz, 1H); 6.76(d, J=2.2 Hz,
1H); 6.97(d, J=8.8 Hz, 1H); 8.67(d, J=1.5 Hz 1H); 10.34(s, 1H).
HPLC analysis on Alltima C.sub.18 column: impurities<2% (column
size 4.6.times.150 mm; mobile phase 25% acetonitrile+75% 0.1M
phosphate buffer (pH 2.5); detector UV 210 nm; sample concentration
1.0 mg/ml; flow rate 1.5 mL/min). Anal. Calcd for
C.sub.19H.sub.29N.sub.3O.sub.3, %: C, 65.68; H, 8.41; N, 12.09.
Found, %: C, 65.65; H, 8.54; N, 12.09.
EXAMPLE 174
8-[4-(3-Fluorophenyl)-piperazin-1-yl]-8-oxooctanoic Acid
Hydroxyamide (PX118859)
[1111] The title compound was obtained using methods analogous to
those described above. M.p. 149-150.5.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO) .delta.: 1.19-1.37(m, 4H); 1.39-1.58(m, 4H);
1.93(t, J=7.5 Hz, 2H); 2.32(t, J=7.4 Hz, 2H); 2.88-3.04(m, 4H);
3.54-3.65(m, 4H); 6.93-7.22(m, 4H); 8.65(br s, 1H); 10.32(s, 1H).
HPLC analysis on Alltima C.sub.18: .about.1% impurities (column
size 4.6.times.150 mm; mobile phase 35% acetonitrile+65% 0.1M
phosphate buffer (pH 2.5); detector UV 220 nm; sample concentration
0.5 mg/ml; flow rate 1.5 mL/min). Anal. Calcd. for
C.sub.18H.sub.26FN.sub.3O.sub.3, %: C, 61.52; H, 7.46; N, 11.96.
Found, %: C 61.45, H 7.48, N 11.88
EXAMPLE 175
8-Oxo-8-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-octanoic Acid
Hydroxyamide (PX118860)
[1112] The title compound was obtained using methods analogous to
those described above. M.p. 126-128.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO) .delta.: 1.16-1.37(m, 4H); 1.38.1.59(m, 4H);
1.93(t, J=7.4 Hz, 2H); 2.33(t, J=7.0 Hz, 2H); 3.14.3.39(m, 4H,
overlapped with a signal of water); 3.52-3.65(m, 4H); 7.09(d, J=7.6
Hz, 1H); 7.18(s, 1H); 7.22(d, J=8.4 Hz, 1H); 7.43(t, J=8.0 Hz, 1H);
8.64(s, 1H); 10.32(s, 1H). HPLC analysis on Omnispher 5 C.sub.18:
<1% impurities (column size 4.6.times.150 mm; mobile phase 40%
acetonitrile+60% 0.1M phosphate buffer (pH 2.5); detector UV 254
nm; sample concentration 0.5 mg/ml; flow rate 1.5 mL/min). Anal.
Calcd for C.sub.19H.sub.26F.sub.3N.sub.3O.sub.3, %: C, 56.85; H,
6.53; N, 10.47. Found, %: C, 56.62; H, 6.48; N, 10.40.
EXAMPLE 176
8-{4-[Bis-(4-fluorophenyl)-methyl]-piperazin-1-yl}-8-oxo Octanoic
Acid Hydroxyamide (PX118898)
[1113] The title compound was obtained using methods analogous to
those described above. M.p. foam. .sup.1H NMR (DMSO-d.sub.6, HMDSO)
.delta.: 1.16-1.35(m, 4H); 1.38-1.58(m, 4H); 1.91(t, J=7.4 Hz, 2H);
2.15-2.30(m, 6H); 3.52-3.65(m, 4H, overlapped with a signal of
water); 4,39(s, 1H); 7.13(t, J=8.6 Hz, 4H); 7.44(dd, J=8.6 and 5.6
Hz, 4H); 8.65(br s, 1H); 10.31 (br s, 1H). HPLC analysis on Alltima
C.sub.18: .about.3.5% impurities. (column size 4.6.times.150 mm;
mobile phase 70% acetonitrile+30% 0.1M phosphate buffer (pH 2.5);
detector UV 220 nm; sample concentration 1.0 mg/ml; flow rate 1.3
mL/min). Anal. Calcd for
C.sub.25H.sub.31F.sub.2N.sub.3O.sub.3*0.25H.sub.2O, %: C, 64.71; H,
6.84; N, 9.06. Found, %: C 64.50, H 6.81, N 8.90.
EXAMPLE 177
8-(3-Methyl-4-m-tolyl-piperazin-1-yl)-8-oxo Octanoic Acid
Hydroxyamide (PX118899)
[1114] The title compound was obtained using methods analogous to
those described above. M.p. 75-76.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO) .delta.: 0.82 and 0.90(d and d, J=6.6 Hz,
3H); 1.14-1.35(m, 4H); 1.39-1.59(m, 4H); 1.93(t, J=7.2 Hz, 2H);
2.24(s, 3H); 2.13-2.42(m, 2H); 2.80-3.53(m, 5H, partly overlapped
with a signal of H.sub.2O); 3.62-4.31(m, 2H); 6.59(d, J=7.8 Hz,
1H); 6.69(d, J=7.8 Hz, 1H); 6.72(s, 1H); 7.09(t, J=7.8 Hz, 1H);
8.65(s, 1H); 10.32(s, 1H). HPLC analysis on Omnispher 5 C.sub.18:
.about.1.8% impurities (column size 4.6.times.150 mm; mobile phase
30% acetonitrile+70% 0.1M phosphate buffer (pH 2.5); detector UV
220 nm; sample concentration 1.0 mg/ml; flow rate 1.2 mL/min).
Anal. Calcd. for C.sub.20H.sub.31N.sub.3O.sub.3, %: C, 66.45; H,
8.64; N, 11.62. Found, %: C, 66.43; H, 8.67; N, 11.52.
EXAMPLE 178
8-[4-(2-1H-Indol-3-yl-acetyl)-piperazin-I-yl]-8-oxo Octanoic Acid
Hydroxyamide (PX118900)
[1115] The title compound was obtained using methods analogous to
those described above. M.p. foam. .sup.1H NMR (DMSO-d.sub.6, HMDSO)
.delta.: 1.10-1.31(m, 4H); 1.34-1.56(m, 4H); 1.93(t, J=7.2 Hz, 2H);
2.18-2.35(m, 2H); 3.20-3.58(m, 8H, overlapped with a signal of
H.sub.2O); 3.79(s, 2H); 6.96(t, J=7.0 Hz, 1H); 7.07(t, J=7.0 Hz,
1H); 7.21 (s, 1H); 7.34(d, J=7.8 Hz, 1H); 7.55(d, J=7.8 Hz, 1H);
8.65(s, 1H); 10.32(s, 1H); 10.93(s, 1H). HPLC analysis on Alltima
C.sub.18: .about.7.5% impurities (column size 4.6.times.150 mm;
mobile phase 30% acetonitrile+70% 0.1M phosphate buffer (pH 2.5);
detector UV 220 nm; sample concentration 1.0 mg/ml; flow rate 1.0
mL/min). Anal. Calcd. for
C.sub.22H.sub.30N.sub.4O.sub.4*0.1H.sub.2O*- 0.1 EtOAc., containing
3% of inorganic impurities, %: C, 61.39; H, 7.13; N, 12.78. Found,
%: C 61.45, H 7.08, N 12.81.
EXAMPLE 179
8-(4-Diphenylacetyl-piperazin-I-yl)-8-oxo Octanoic Acid
Hydroxyamide (PX118901)
[1116] The title compound was obtained using methods analogous to
those described above. M.p. foam. .sup.1H NMR (DMSO-d.sub.6, HMDSO)
.delta.: 1.14-1.30(m, 4H); 1.34-1.54(m, 4H); 1.93(t, J=7.2 Hz, 2H);
2.17-2.32(m, 2H); 3.09-3.21(m, 2H); 3.30-3.58(m, 6H, overlapped
with a signal of H.sub.2O); 5.55(s, 1H); 7.15-7.37(m, 10H); 8.66(s,
1H); 0.33(s, 1H). HPLC analysis on Omnispher 5 C.sub.18:
.about.2.2% impurities. (column size 4.6.times.150 mm; mobile phase
60% acetonitrile+40% 0.1M phosphate buffer (pH 2.5); detector UV
220 nm; sample concentration 0.5 mg/ml; flow rate 1.2 mL/min.) Anal
Calcd for C.sub.26H.sub.33N.sub.3O.sub.4*0.5 MeOH, %: C, 68.07; H,
7.54; N, 8.99. Found, %: C, 68.04; H, 7.23; N, 8.99.
EXAMPLE 180
8-[4-(2-Naphthalen-2-yl-acetyl)-piperazin-1-yl]-8-oxo Octanoic Acid
Hydroxyamide (PX118902)
[1117] The title compound was obtained using methods analogous to
those described above. M. p. foam. .sup.1H NMR (DMSO-d.sub.6,
HMDSO) .delta.: 1.12-1.32(m, 4H); 1.35-1.56(m, 4H); 1.92(t, J=7.4
Hz, 2H); 2.28(t, J=6.8 Hz, 2H); 3.26-3.58(m, 8H, overlapped with a
signal of H.sub.2O); 3.91 (s, 2H); 7.39(dd, J=8.4 and 1.8 Hz, 1H);
7.45-7.54(m, 2H); 7.73(s, 1H); 7.79-7.92(m, 3H); 8.67(s, 1H);
10.33(s, 1H). HPLC analysis on Alltima C.sub.18: .about.5%
impurities (column size 4.6.times.150 mm; mobile phase 40%
acetonitrile+60% 0.1M phosphate buffer (pH 2.5); detector UV 220
nm; sample concentration 0.5 mg/ml; flow rate 1.3 mL/min.) Anal.
Calcd. for C.sub.24H.sub.31N.sub.3O.sub.4*0.75H.sub.2O, %: C,
65.66; H, 7.46; N, 9.57. Found, %: C 65.52, H 7.40, N 9.43.
EXAMPLE 181
8-{4-[4-(1-Hydroxyimino-ethyl)-phenyl]-piperazin-1-yl}-8-oxo
Octanoic Acid Hydroxyamide (PX118903)
[1118] The title compound was obtained using methods analogous to
those described above. M.p. 147-147.5.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO) .delta.: 1.18-1.35(m, 4H); 1.37-1.57(m, 4H);
1.93(t, J=7.4 Hz, 2H); 2.09(s, 3H); 2.33(t, J=7.2 Hz, 2H);
3.06-3.25(m, 4H); 3.51-3.65(m, 4H); 6.94(d, J=8.8 Hz, 2H); 7.51(d,
J=8.8 Hz, 2H); 8.65(s, 1H); 10.32(s, 1H); 10.86(s, 1H). HPLC
analysis on Zorbax SB 5 C.sub.18: .about.5% of acetophenone
derivative (sample contains ca. 5% of the corresponding
methylketone
8-[4-(4-acetylphenyl)-1-piperazinyl]-N-hydroxy-8-oxooctanami- de).
(column size 4.6.times.150 mm; mobile phase acetonitrile-0.1M
phosphate buffer (pH 2.5), gradient 15 min from 20:80 to 100:0;
detector UV 254 nm; sample concentration 0.5 mg/ml; flow rate 1.0
mL/min.) Anal. Calcd. for C.sub.20H.sub.30N.sub.4O.sub.4 containing
5% of the acetophenone C.sub.20H.sub.29N.sub.3O.sub.4, %: C, 61.63;
H, 7.75; N, 14.20. Found, %: C 61.67, H 7.76, N 13.76.
EXAMPLE 182
8-Oxo-8[4-(3-phenylallyl)-piperazin-1-yl]-octanoic Acid
Hydroxyamide (PX118904)
[1119] The title compound was obtained using methods analogous to
those described above. M. p. foam. .sup.1H NMR (DMSO-d.sub.6,
HMDSO) .delta.: 1.14-1.32(m, 4H); 1.36-1.55(m, 4H); 1.93(t, J=7.3
Hz, 2H); 2.19-2.45(m, 6H); 3.10(d, J=6.6 Hz, 2H); 3.27-3.51(m, 4H,
overlapped with a signal of H.sub.2O); 6.29(dt, J=6.60 and 16.2 Hz,
1H); 6.54(d, J=16.2 Hz, 1H); 7.15-7.48(m, 3H); 7.44(d, J=6.6 Hz,
2H); 8.67(br s, H); 10.33(s, 1H). HPLC analysis on Alltima
C.sub.18: .about.5% impurities (column size 4.6.times.150 mm;
mobile phase 20% acetonitrile+80% 0.1M phosphate buffer (pH 2.5);
detector UV 220 nm; sample concentration 1.0 mg/ml; flow rate 1.5
mL/min.) Anal. Calcd. for
C.sub.21H.sub.31N.sub.3O.sub.3*0.5H.sub.2O, %: C, 65.94; H, 8.43;
N, 10.99. Found, %: C, 66.05; H, 8.28; N, 10.94.
EXAMPLE 183
8-[4(2-Naphthalen-2-yl-ethyl)-piperazin-1-yl]-8-oxo Octanoic Acid
Hydroxyamide (PX118908)
[1120] The title compound was obtained using methods analogous to
those described above. M.p. 118-120.degree. C. 1H NMR
(DMSO-d.sub.6, HMDSO) .delta.: 1.16-1.34(m, 4H); 1.36-1.56(m, 4H);
1.92(t, J=7.3 Hz, 2H); 2.27(t, J=7.6 Hz, 2H); 2.34-2.55(m, 4H,
overlapped with a signal of DMSO); 2.63(t, J=8.4 Hz, 2H); 2.92(t,
J=8.4 Hz, 2H); 3.28-3.52 (m, 4H, overlapped with a signal of
H.sub.2O); 7.37-7.53(m, 3H); 7.73(s, 1H); 7.77-7.91(m, 3H); 8.67(s,
1H); 10.33(s, 1H). HPLC analysis on Omnispher 5 C.sub.18:
.about.1.5% impurities (column size 4.6.times.150 mm; mobile phase
25% acetonitrile+75% 0.1M phosphate buffer (pH 2.5); detector UV
220 nm; sample concentration 0.5 mg/ml; flow rate 1.2 mL/min.)
Anal. Calcd. for C.sub.24H.sub.33N.sub.3O.sub.3, %: C, 70.04; H,
8.08; N, 10.21. Found, %: C, 69.31; H, 8.11; N, 10.20.
EXAMPLE 184
8-[4-(2,2-Diphenyl-ethyl)-piperazin-1-yl]-8-oxo Octanoic Acid
Hydroxyamide (PX118909)
[1121] The title compound was obtained using methods analogous to
those described above. M.p. 117-118.degree. C. .sup.1H NMR
(DMSO-d.sub.6, HMDSO) .delta.: 1.12-1.31(m, 4H); 1.34-1.54(m, 4H);
1.91(t, J=7.4 Hz, 2H); 2.23(t, J=7.4 Hz, 2H); 2.31-2.48(m, 4H,
overlapped with a signal of DMSO); 2.94(d, J=7.6 Hz, 2H); 3.26-3.48
(m, 4H, overlapped with a signal of H.sub.2O); 4.26(t, J=7.6 Hz,
1H); 7.09-7.40(m, 10H); 8.65(s, 1H); 10.31(s, 1H). HPLC analysis on
Alltima C.sub.18: <1% impurities. (column size: 4.6.times.150
mm; mobile phase 25% acetonitrile+75% 0.1M phosphate buffer (pH
2.5); detector UV 215 nm; sample concentration 1.0 mg/ml; flow rate
1.15 mL/min.) Anal. Calcd. for C.sub.26H.sub.35N.sub.3O.- sub.3, %:
C, 71.37; H, 8.06; N, 9.60. Found, %: C, 71.01; H, 8.11; N,
9.59.
[1122] Biological Activity
[1123] Candidate compounds were assessed for their ability to
inhibit deacetylase activity (biochemical assays) and to inhibit
cell proliferation (cell-based antiproliferation assays), as
described below.
[1124] Primary Assay (1): Deacetylase Activity
[1125] Briefly, this assay relies on the release of radioactive
acetate from a radioactively labelled histone fragment by the
action of HDAC enzyme. Test compounds, which inhibit HDAC, reduce
the yield of radioactive acetate. Signal (e.g., scintillation
counts) measured in the presence and absence of a test compound
provide an indication of that compound's ability to inhibit HDAC
activity. Decreased activity indicates increased inhibition by the
test compound.
[1126] The histone fragment was an N-terminal sequence from histone
H4, and it was labelled with radioactively labelled acetyl groups
using tritiated acetylcoenzyme A (coA) in conjunction with an
enzyme which is the histone acetyltransferase domain of the
transcriptional coactivator p300. 0.33 mg of peptide H4 (the
N-terminal 20 amino acids of histone H4, synthesized using
conventional methods) were incubated with His6-tagged p300 histone
acetyltransferase domain (amino acids 1195-1673, expressed in E.
coli strain BLR(DE3)pLysS (Novagen, Cat. No. 69451-3) and 3H-acetyl
coA (10 .mu.L of 3.95 Ci/mmol; from Amersham) in a total volume of
300 .mu.L of HAT buffer (50 mM TrisCl pH 8, 5% glycerol, 50 mM KCl,
0.1 mM ethylenediaminetetraacetic acid (EDTA), 1 mM dithiothreitol
(DTT) and 1 mM 4-(2-aminoethyl)-benzenesulfonylfluoride (AEBSF)).
The mixture was incubated at 30.degree. C. for 45 min after which
the His-p300 was removed using nickel-trinitriloacetic acid agarose
(Qiagen, Cat No. 30210). The acetylated peptide was then separated
from free acetyl coA by size exclusion chromatography on Sephadex
G-15 (Sigma G-15-120), using distilled H.sub.2O as the mobile
phase.
[1127] After purification of the radiolabelled histone fragment, it
was incubated with a source of HDAC (e.g., an extract of HeLa cells
(a rich source of HDAC), recombinantly produced HDAC1 or HDAC2) and
any released acetate was extracted into an organic phase and
quantitatively determined using scintillation counting. By
including a test compound with the source of HDAC, that compound's
ability to inhibit the HDAC was determined.
[1128] Primary Assay (2): Deacetylase Activity: Fluorescent
Assay
[1129] Alternatively, the activity of the compounds as HDAC
inhibitors was determined using a commercially available
fluorescent assay kit: (Fluor de Lys.TM., BioMol Research Labs,
Inc., Plymouth Meeting, USA). HeLa extract was incubated for 1 hour
at 37.degree. C. in assay buffer (25 mM HEPES, 137 mM NaCl, 2.7 mM
KCl, 1 mM MgCl.sub.2, pH 8.0) with 15 .mu.M acetylated substrate in
the presence of test compound (HDAC inhibitor). The extent of
deacetylation was determined by the addition of 50 .mu.L of a
1-in-500 dilution of Developer, and measurement of the fluorescence
(excitation 355 nm, emission 460 nm), according to the instructions
provided with the kit.
[1130] Extensive comparative studies have shown that Primary Assay
(1) and Primary Assay (2), discussed above, yield equivalent
results. Primary Assay results reported herein are (a) exclusively
from (1); (b) exclusively from (2); or (c) from both (1) and
(2).
[1131] HeLa Cell Extract
[1132] The HeLa cell extract was made from HeLa cells (ATCC Ref.
No. CCL-2) by freeze-thawing three times in 60 mM TrisCl pH 8.0,
450 mM NaCl, 30% glycerol. Two cell volumes of extraction buffer
were used, and particulate material was centrifuged out (20800 g,
4.degree. C., 10 min). The supernatant extract having deacetylase
activity was aliquotted and frozen for storage.
[1133] Recombinantly Produced HDAC1 and HDAC2
[1134] Recombinant plasmids were prepared as follows.
[1135] Full length human HDAC1 was cloned by PCR using a
.lambda.gt11 Jurkat cDNA library (Clontech-HL5012b). The amplified
fragment was inserted into the EcoRI-SalI sites of pFlag-CTC vector
(Sigma-E5394), in frame with the Flag tag. A second PCR was carried
out in order to amplify a fragment containing the HDAC1 sequence
fused to the Flag tag. The resulting fragment was subcloned into
the EcoRI-Sac1 sites of the baculovirus transfer vector pAcHTL-C
(Pharmingen-21466P).
[1136] Full length mouse HDAC2 was subcloned into pAcHLT-A
baculovirus transfer vector (Pharmingen-21464P) by PCR
amplification of the EcoRI-Sac1 fragment from a HDAC2-pFlag-CTC
construct.
[1137] Recombinant protein expression and purification was
performed as follows.
[1138] HDAC1 and HDAC2 recombinant baculoviruses were constructed
using BaculoGold Transfection Kit (Pharmingen-554740). Transfer
vectors were co-transfected into SF9 Insect cells
(Pharmingen-21300C). Amplification of recombinant viruses was
performed according to the Pharmingen Instruction Manual. SF9 cells
were maintained in serum-free SF900 medium (Gibco 10902-096).
[1139] For protein production, 2.times.10.sup.7 cells were infected
with the appropriate recombinant virus for 3 days. Cells were then
harvested and spun at 3,000 rpm for 5 minutes. They were then
washed twice in PBS and resuspended in 2 pellet volumes of lysis
buffer (25 mM HEPES pH 7.9, 0.1 mM EDTA, 400 mM KCl, 10% glycerol,
0.1% NP-40, 1 mM AEBSF). Resuspended cells were frozen on dry ice
and thawed at 37.degree. C. 3 times and centrifuged for 10 minutes
at 14,000 rpm. The supernatant was collected and incubated with 300
.mu.l of 50% Ni-NTA agarose bead slurry (Qiagen-30210). Incubation
was carried out at 4.degree. C. for 1 hour on a rotating wheel. The
slurry was then centrifuged at 500 g for 5 minutes. Beads were
washed twice in 1 ml of wash buffer (25 mM HEPES pH 7.9, 0.1 mM
EDTA, 150 mM KCl, 10% glycerol, 0.1% NP-40, 1 mM AEBSF). Protein
was eluted 3 times in 300 .mu.l elution buffer (25 mM HEPES pH 7.9,
0.1 mM EDTA, 250 mM KCl, 10% glycerol, 0.1% NP-40, 1 mM AEBSF)
containing increasing concentrations of imidazole: 0.2 M, 0.5 M and
1 M. Each elution was performed for 5 minutes at room temperature.
Eluted protein was kept in 50% glycerol at -70.degree. C.
[1140] Assay Method
[1141] A source of HDAC (e.g., 2 .mu.L of crude HeLa extract, 5
.mu.L of HDAC1 or HDAC2; in elution buffer, as above) was incubated
with 3 .mu.L of radioactively labelled peptide along with
appropriate dilutions of candidate compounds (1.5 .mu.L) in a total
volume of 150 .mu.L of buffer (20 mM Tris pH 7.4, 10% glycerol).
The reaction was carried out at 37.degree. C. for one hour, after
which the reaction was stopped by adding 20 .mu.L of 1 M HCl/0.4 M
sodium acetate. Then, 750 .mu.L of ethyl acetate was added, the
samples vortexed and, after centrifugation (14000 rpm, 5 min), 600
.mu.L from the upper phase were transferred to a vial containing 3
mL of scintillation liquid (UltimaGold, Packard, Cat. No.
6013329).
[1142] Radioactivity was measured using a Tri-Carb 2100TR Liquid
Scintillation Analyzer (Packard).
[1143] Percent activity (% activity) for each test compound was
calculated as:
% activity={(S.sup.C-B)/(S.sup.o-B)).times.100
[1144] wherein S.sup.C denotes signal measured in the presence of
enzyme and the compound being tested, S.sup.o denotes signal
measured in the presence of enzyme but in the absence of the
compound being tested, and B denotes the background signal measured
in the absence of both enzyme and compound being tested. The IC50
corresponds to the concentration which achieves 50% activity.
[1145] IC50 data for several compounds of the present invention, as
determined using this assay, are also shown in Table 1, below.
[1146] Measurement of cell viability in the presence of increasing
concentration of test compound at different time points is used to
assess both cytotoxicity and the effect of the compound on cell
proliferation.
[1147] Secondary Assay: Cell Proliferation
[1148] Compounds with HDAC inhibition activity, as determined using
the primary assay, were subsequently evaluated using secondary
cell-based assays. The following cell lines were used:
[1149] HeLa--Human cervical adenocarcinoma cell line (ATCC ref. No.
CCL-2).
[1150] K11--HPV E7 transformed human keratinocyte line provided by
Pidder Jansen-Duerr, Institut fur Biomedizinische Alternsforschung,
Innsbruck, Austria.
[1151] NHEK-Ad--Primary human adult keratinocyte line (Cambrex
Corp., East Rutherford, N.J., USA).
[1152] JURKAT--Human T-cell line (ATCC no. TIB-152).
[1153] Assay Method
[1154] Cells were cultured, exposed to candidate compounds, and
incubated for a time, and the number of viable cells was then
assessed using the Cell Proliferation Reagent WST-1 from Boehringer
Mannheim (Cat. No. 1 644 807), described below.
[1155] Cells were plated in 96-well plates at 3-10.times.10.sup.3
cells/well in 100 .mu.L of culture medium. The following day,
different concentrations of candidate compounds were added and the
cells incubated at 37.degree. C. for 48 h. Subsequently, 10
.mu.L/well of WST-1 reagent was added and the cells reincubated for
1 hour. After the incubation time, absorbance was measured.
[1156] WST-1 is a tetrazolium salt which is cleaved to formazan dye
by cellular enzymes. An expansion in the number of viable cells
results in an increase in the overall activity of mitochondrial
dehydrogenases in the sample. This augmentation in the enzyme
activity leads to an increase in the amount of formazan dye formed,
which directly correlates to the number of metabolically active
cells in the culture. The formazan dye produced is quantified by a
scanning multiwell spectrophotometer by measuring the absorbance of
the dye solution at 450 nm wavelength (reference wavelength 690
nm).
[1157] Percent activity (% activity) in reducing the number of
viable cells was calculated for each test compound as:
% activity=(S.sup.C-B)/(S.sup.o-B)}.times.100
[1158] wherein S.sup.C denotes signal measured in the presence of
the compound being tested, S.sup.o denotes signal measured in the
absence of the compound being tested, and B denotes the background
signal measured in blank wells containing medium only. The IC50
corresponds to the concentration which achieves 50% activity. IC50
values were calculated using the software package Prism 3.0
(GraphPad Software Inc., San Diego, Calif.), setting top value at
100 and bottom value at 0.
[1159] IC50 data for several compounds of the present invention, as
determined using this assay, are also shown in Table 2, below.
[1160] Measurement of cell viability in the presence of increasing
concentration of test compound at different time points is used to
assess both cytotoxicity and the effect of the compound on cell
proliferation.
[1161] Screening in Mice with Intraperitoneal P388 Tumour
[1162] Female B6D2F1 hybrid mice weighing 19-23 grams were
inoculated with the tumour cell line P388 (10.sup.6 cells in 0.2
mL) intraperitoneally (IP). Inoculation of tumour cells was
performed on a Friday and treatment with compounds at a dose of 64
.mu.mol/kg/day started on Day 3 (Monday). The compounds were given
as a single daily IP dose for five consecutive days. Compounds were
dissolved in DMSO, at a concentration corresponding to 50 .mu.L
injection volume per treatment. Treatments were given at the same
hour of the day (within one hour). Five mice in each group were
treated with compounds, and with each series of experiments,
control groups (not treated, and DMSO-treated) were included.
Moribund mice were euthanised, and the day of death was recorded.
Log-rank analysis of the survival data was performed using the
statistical software SAS v8.1 (SAS Institute, Cary, N.C., USA).
[1163] Biological Data
[1164] IC50 (or percent activity) data for several compounds of the
present invention, as determined using the assays described above
are summarised in Table 1 and Table 2, below.
[1165] The results of in vivo studies of mice with intraperitoneal
P388 tumour for several compounds of the present invention, using
the methods described above, are summarised in Table 3.
2TABLE 1 Biochemical Assay Data HDAC Inhibition Compound (IC50
unless otherwise specified) No. Ref. HeLa HDAC1 HDAC2 1 TSA 5 nM 15
nM 17 nM 2 SAHA 189 nM -- -- 3 PX117403 28% @ 500 nM -- -- 4
PX117404 35% @ 500 nM -- -- 5 PX117764 785 nM -- -- 6 PX117768 175
nM -- -- 7 PX118490 59% @ 100 nM -- -- 8 PX118491 47% @ 100 nM --
-- 9 PX118807 60% @ 100 nM -- -- 10 PX118810 46 nM -- -- 11
PX118811 42 nM -- -- 12 PX118812 26 nM -- -- 13 PX118791 36 nM --
-- 14 PX118792 34 nM -- -- 15 PX118793 188 nM -- -- 16 PX118794 74
nM -- -- 17 PX118830 133 nM -- -- 18 PX118831 194 nM -- -- 19
PX118832 212 nM -- -- 20 PX118844 286 nM -- -- 21 PX118846 3.4 nM
-- -- 22 PX118847 31 nM -- -- 23 PX118848 44% @100 nM -- -- 24
PX118849 26 nM -- -- 25 PX118850 70 nM -- --
[1166]
3TABLE 2 Cell-Based Antiproliferation Assay Data Cell Proliferation
Inhibition WST-1 Compound (IC50 unless otherwise specified) No.
Ref. HeLa K11 NHEK-AD Jurkat TSA 350 nM 0.38 .mu.M 0.2 .mu.M 42 nM
Oxamflatin -- 4.82 .mu.M 3.53 .mu.M 170 nM MS-275 -- 9.16 .mu.M 3.1
.mu.M 365 nM SAHA -- 6.82 .mu.M 5.37 .mu.M 750 nM 1 PX117403 -- --
-- -- 2 PX117404 -- -- -- -- 3 PX117764 29.2 .mu.M 9.45 .mu.M --
2.68 .mu.M 4 PX117768 3.30 .mu.M 8.67 .mu.M -- 1.04 .mu.M 5
PX118490 1.00 .mu.M 2.49 .mu.M -- 460 nM 6 PX118491 18 .mu.M 8.24
.mu.M -- 3.21 .mu.M
[1167]
4TABLE 3 In Vivo Studies of Mice with Intraperitoneal P388 Tumour
Log rank Wilcoxon No. of Compound statistic statistic mice --
6.8173 1556.0 25 DMSO 6.4056 1290.0 20 PX118490 -3.3797 -654.0 5
PX118807 -4.6177 -750.0 5 PX118871 -3.4210 -605.0 5 PX118875
-3.0949 -525.0 5 PX118882 -4.9869 -613.0 5 PX118893 -3.5651 -725.0
5 PX118905 -4.0610 -565.0 5 PX118907 -4.1247 -817.0 5 PX118910
-9.6221 -869.0 5
[1168] The foregoing has described the principles, preferred
embodiments, and modes of operation of the present invention.
However, the invention should not be construed as limited to the
particular embodiments discussed. Instead, the above-described
embodiments should be regarded as illustrative rather than
restrictive, and it should be appreciated that variations may be
made in those embodiments by workers skilled in the art without
departing from the scope of the present Invention as set out in the
appended claims.
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